WORLD INTELLECTUAL PROPERTY ORGANIZATION
International Bureau
PCT
INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(51) International Patent Classification 6 ;
(11) International Publication Number:
WO 99/32436
C07C 275/24, C07D 213/02, 333/02,
A61K 31/17, 31/38, 31/44
Al
(43) International Publication Date:
1 July 1999 (01.07.99)
(21) International Application Number: PCT/US98/26081
(22) International Filing Date: 22 December 1998 (22.12.98)
(30) Priority Data:
08/996,344
22 December 1997 (22.12.97) US
(71) Applicant: BAYER CORPORATION [US/US]; 100 Bayer
Road, Pittsburg, PA 15205 (US).
(72) Inventors: MILLER, Scott; 220 Lindenwood Drive, Exton,
PA 19341 (US). OSTERHOUT, Martin; 3217 Quiet Mill
Road, Raleigh, NC 27612 (US). DUMAS, Jacques; 821
Beechwood Road, Orange, CT 06477 (US). KHIRE,
Uday; 101 Tanglewood Drive, Hamden, CT 06518 (US).
LOWINGER, Timothy, Bruno; 5-7, #1203 Chitose-cho,
Nishinomiya, Hyogo 662-0046 (JP). RIEDL, Bernd; 13
Cedrus Court, Branford, CT 06405 (US). SCOTT, William,
J.; 210 Saddle Hill Drive, Guilford, CT 06437 (US).
SMITH, Roger, A.; 65 Winterhill Road, Madison, CT 06443
(US). WOOD, Jill, E.; 72 Pickwick Road, Hamden, CT
06517 (US). GUNN, David; 40 Wood Street, Hamden,
CT 06517 (US). RODRIGUEZ, Mareli; 281 Durham Road,
Guilford, CT 06437 (US). WANG, Ming; 112 Hoyt Street
#4F, Stamford, CT 06905 (US).
(74) Agents: TRA VERSO, Richard, J. et al.; Millen, White, Zelano
& Branigan, P.C., Arlington Courthouse Plaza 1, Suite 1400,
2200 Clarendon Boulevard, Arlington, VA 22201 (US).
(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD,
GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP,
KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK,
MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG,
SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW,
ARIPO patent (GH, GM, KE, LS, MW, SD, SZ, UG, ZW),
Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
European patent (AT, BE, CH, CY, DE, DK, ES, FI, FR,
GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF,
BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN,
TD, TG).
Published
With international search report.
(54) Title: INHIBITION OF RAF KINASE USING SYMMETRICAL AND UNSYMMETRICAL SUBSTITUTED DIPHENYL UREAS
(57) Abstract
This invention relates to the use of a group of aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use
in such therapy.
FOR THE PURPOSES OF INFORMATION ONLY
Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
AL
Albania
ES
Spain
LS
Lesotho
SI
Slovenia
AM
Armenia
FI
Finland
LT
Lithuania
SK
Slovakia
AT
Austria
FR
France
LU
Luxembourg
SN
Senegal
AU
Australia
GA
Gabon
LV
Latvia
sz
Swaziland
AZ
Azerbaijan
GB
United Kingdom
MC
Monaco
TD
Chad
BA
Bosnia and Herzegovina
GE
Georgia
MD
Republic of Moldova
TG
Togo
BB
Barbados
GH
Ghana
MG
Madagascar
TJ
Tajikistan
BE
Belgium
GN
Guinea
MK
The former Yugoslav
TM
Turkmenistan
BF
Burkina Faso
GR
Greece
Republic of Macedonia
TR
Turkey
BG
Bulgaria
HU
Hungary
ML
Mali
TT
Trinidad and Tobago
BJ
Benin
IE
Ireland
MN
Mongolia
UA
Ukraine
BR
Brazil
IL
Israel
MR
Mauritania
UG
Uganda
BY
Belarus
IS
Iceland
MW
Malawi
us
United States of America
CA
Canada
IT
Italy
MX
Mexico
uz
Uzbekistan
CF
Central African Republic
JP
Japan
NE
Niger
VN
Viet Nam
CG
Congo
KE
Kenya
NL
Netherlands
YU
Yugoslavia
CH
Switzerland
KG
Kyrgyzstan
NO
Norway
ZW
Zimbabwe
CI
Cdte d'lvoire
KP
Democratic People's
NZ
New Zealand
CM
Cameroon
Republic of Korea
PL
Poland
CN
China
KR
Republic of Korea
PT
Portugal
cu
Cuba
KZ
Kazakstan
RO
Romania
cz
Czech Republic
LC
Saint Lucia
RU
Russian Federation
DE
Germany
LI
Liechtenstein
SD
Sudan
DK
Denmark
LK
Sri Lanka
SE
Sweden
EE
Estonia
LR
Liberia
SG
Singapore
WO 99/32436
PCT/US98/26081
INHIBITION OF RAF KINASE USING SYMMETRICAL AND
UNSYMMETRICAL SUBSTITUTED DIPHENYL UREAS
Field of the Invention
This invention relates to the use of a group of aryl ureas in treating raf mediated
diseases, and pharmaceutical compositions for use in such therapy.
Background of the Invention
The p21 ras oncogene is a major contributor to the development and progression of
human solid cancers and is mutated in 30% of all human cancers (Bolton et al. Ann.
Rep. Med. Chem. 1994, 29, 165-74; Bos. Cancer Res. 1989, 49, 4682-9). In its
normal, unmutated form, the ras protein is a key element of the signal transduction
cascade directed by growth factor receptors in almost all tissues (Avruch et al. Trends
Biochem. Set 1994, 19, 279-83). Biochemically, ras is a guanine nucleotide binding
protein, and cycling between a GTP-bound activated and a GDP-bound resting form is
strictly controlled by ras' endogenous GTPase activity and other regulatory proteins.
In the ras mutants in cancer cells, the endogenous GTPase activity is alleviated and,
therefore, the protein delivers constitutive growth signals to downstream effectors
such as the enzyme raf kinase. This leads to the cancerous growth of the cells which
carry these mutants (Magnuson et al. Semin. Cancer Biol 1994, 5, 247-53). It has
been shown that inhibiting the effect of active ras by inhibiting the raf kinase
signaling pathway by administration of deactivating antibodies to raf kinase or by co-
expression of dominant negative raf kinase or dominant negative MEK, the substrate
of raf kinase, leads to the reversion of transformed cells to the normal growth
phenotype (see: Daum et al. Trends Biochem. Set 1994, 79, 474-80; Fridman et al. J.
Biol Chem. 1994, 269, 30105-8. Kolch et al. {Nature 1991, 349, 426-28) have further
indicated that inhibition of raf expression by antisense RNA blocks cell proliferation
WO 99/32436
PCT/US98/26081
in membrane-associated oncogenes. Similarly, inhibition of raf kinase (by antisense
oligodeoxynucleotides) has been correlated in vitro and in vivo with inhibition of the
growth of a variety of human tumor types (Monia et al., Nat Med. 1996, 2, 668-75).
5 Summary of the Invention
The present invention provides compounds which are inhibitors of the enzyme raf
kinase. Since the enzyme is a downstream effector of p21 ras , the instant inhibitors are
useful in pharmaceutical compositions for human or veterinary use where inhibition
of the raf kinase pathway is indicated, e.g., in the treatment of tumors and/or
10 cancerous cell growth mediated by raf kinase. In particular, the compounds are useful
in the treatment of human or animal cancers, e.g., murine, solid cancers, since the
progression of these cancers is dependent upon the ras protein signal transduction
cascade and therefore susceptible to treatment by interruption of the cascade, i.e., by
inhibiting raf kinase. Accordingly, the compounds of the invention are useful in
15 treating solid cancers, such as, for example, carcinomas (e.g., of the lungs, pancreas,
thyroid, bladder or colon), myeloid disorders (e.g., myeloid leukemia) or adenomas
(e.g., villous colon adenoma).
The present invention, therefore, provides compounds generally described as aryl
20 ureas, including both aryl and heteroaryl analogues, which inhibit the raf pathway.
The invention also provides a method for treating a raf mediated disease state in
humans or mammals. Thus, the invention is directed to compounds and methods for
the treatment of cancerous cell growth mediated by raf kinase, comprising
administering a compound of Formula I
25 wherein
I
30
2
WO 99/32436
PCT/US98/26081
wherein
A is
,4'
or
_ r4 .
R
5'
R 3 , R 4 , R 5 and R 6 are each, independently, H, halogen, N0 2 , C M0 - alkyl, optionally
substituted by halogen up to perhaloalkyl, CL^-alkoxy, optionally
substituted by halogen up to perhaloalkoxy, C 6 . 12 aryl, optionally
substituted by C M0 alkyl or C,. 10 alkoxy, or C 5 . 12 hetaryl, optionally
substituted by C M0 alkyl or C M0 alkoxy,
and one of R 3 -R 6 can be -X-Y;
or two adjacent R 3 -R 6 can together be an aryl or hetaryl ring with 5-12 atoms,
optionally substituted by C M0 -alkyl, C M0 -alkoxy, C 3 _ 10 -cycloalkyl, C 2 . 10 -alkenyl,
C,. 10 -alkanoyl, C^-aryl, C 5 . 12 -hetaryl; C^-aralkyl, C 6 _ 12 -alkaryl, halogen; NR'R 1 ;
-N0 2 ; -CF 3 ; -COOR 1 ; -NHCOR 1 ; -CN; -CONR'R 1 ; -S0 2 R 2 ; -SOR 2 ; -SR 2 ; in which R 1
is H or CYio-alkyl and R 2 is C,. I0 -alkyl, optionally substituted by halogen, up to
perhalo with -S(0 2 )- optionally incorporated in the aryl or hetaryl ring;
R 4 ' , R 5 and R 6 ' are independently H, halogen, Cj - C 10 alkyl, optionally substituted by
halogen up to perhaloalkyl, or by
N
\
or
O
N
NH
O
Cj -C 10 alkoxy optionally substituted by halogen up to perhaloalkoxy or -X-Y,
and either one of R 4 ', R 5 ' or R 6 ' is -X-Y or two adjacent of R 4 ', R 5 ' and R 6
together are a hetaryl ring with 5-12 atoms optionally substituted by C,., 0 alkyl,
WO 99/32436
PCT/US98/26081
C,. 10 alkoxy, C 3 ., 0 cycloalkyl, C 2 . 10 alkenyl, C,. I0 alkanoyl, C W2 aryl, C 5 _ 12
hetaryl or C M2 aralkyl;
R 6 ' is additionally -NHCOR 1 , - NR 1 COR 1 or N0 2 ;
R 1 is C,. 10 alkyl optionally substituted by halogen up to perhalo;
R 3 ' is H, halogen, C,-C, 0 alkyl optionally substituted by halogen up to perhaloalkyl,
C,-C, 0 alkoxy, optionally substituted by halogen up to perhaloalkoxy;
X is -CH 2 -, -S- -N(CH 3 )-, -NHC(O)- -CH 2 -S-, -S-CH 2 -, -C(O)-, or -O-; and
X is additionally a single bond where Y is pyridyl; and
Y is phenyl, pyridyl, naphthyl, pyridone, pyrazine, pyrimidine, benzodioxane,
benzopyridine or benzothiazole, each optionally substituted by Cj., 0 -alkyl,
C M0 -alkoxy, halogen, OH, -SCH 3 , N0 2 or, where Y is phenyl, by
or a pharmaceutically acceptable salt thereof,
with the proviso that if X is -O- or -S- , R 3 and R 6 ' are H, and Y is phenyl
unsubstituted by OH, then R 6 is alkoxy.
Preferably, R 3 is halogen or C ,_,<,- alkyl, optionally substituted by halogen, up to
perhaloalkyl; R 4 is H, halogen or N0 2 ; R 5 is H, halogen or C M0 - alkyl; and R 6 is H or
C,. I0 - alkoxy. More preferably, R 3 is C^-alkyl, CI, F or CF 3 ; R 4 is H, CI, F or N0 2 ;
R s is H, CI, F or C 4 . 10 -alkyl; and R 6 is H or OCH 3 . Still more preferably, R 3 or R 4 is t-
butyl. X is preferably -CH 2 - or -S- and Y is phenyl or pyridyl, or X is -O- and Y is
preferably phenyl, pyridyl or benzthiazole.
The invention is also directed to a compound of the formula
O
The invention is further directed to a method for the treatment of a cancerous cell
growth mediated by raf kinase, comprising administering a compound of Formula II:
WO 99/32436
PCT/US98/26081
wherein
A is
B
O
N^N
H H
R
5'
n
or
R
4'
10
15
20
25
B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety
of up to 30 carbon atoms with at least one 6-member aromatic structure containing
0-4 members of the group consisting of nitrogen, oxygen and sulfur, wherein if B is
substituted it is substituted by one or more substituents selected from the group
consisting of halogen, up to per-halo, and W n , wherein n is 0-3 and each W is
independently selected from the group consisting of -CN, -CO z R , -C(0)NR R ,
-C(0)-R 7 , -N0 2 , -OR 7 , - SR 7 , - NR 7 R 7 , -NR 7 C(0)OR 7 , -NR 7 C(0)R 7 , C r C 10 alkyl,
C 2 -C 10 alkenyl, C r C 10 alkoxy, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 7 -C 24 alkaryl, C 3 -C 13
heteroaryl, Q-C^ alkheteroaryl, substituted C r C 10 alkyl, substituted C 3 -C 10
cycloalkyl, substituted C 2 -C 10 alkenyl, substituted C r Ci 0 alkoxy, substituted Q-C^
alkheteroaryl and Q-Ar;
wherein if W is a substituted group, it is substituted by one or more
substituents independently selected from the group consisting of -CN, -CO z R ,
-C(0)R 7 , -C(0)NR 7 R 7 , -OR 7 , -SR 7 , -NR 7 R 7 , N0 2 , -NR 7 C(0)R 7 , -NR 7 C(0)OR 7 and
halogen up to per-halo;
wherein each R 7 is independently selected from H, C 2 -Ci„ alkenyl, C,-C 10
alkyl, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 3 -C, 3 hetaryl, C 7 -C 24 alkaryl, Q-C^
alkheteroaryl, up to per-halosubstituted C r C 10 alkyl, up to per-halosubstituted C 2 -
C 10 alkenyl, up to per-halosubstituted C 3 -Ci 0 cycloalkyl, up to per-halosubstituted
C 6 -C M aryl and up to per-halosubstituted C 3 -Ci 3 hetaryl,
wherein Q is -O-, -S-, -N(R 7 )-, -C(O)-, -CH(OH)-, -(CH^O-,
5
WO 99/32436
PCT/US98/26081
-NR 7 C(0)NR 7 R 7 -, -NR 7 C(0)-, -C(0)NR 7 -, -(CH 2 ) m S-, -(CH 2 ) m N(R 7 )-, -0(CH 2 ) m -,
-CHX\ -CXY, -S-(CH 2 ) m - and -N(R 7 )(CH 2 ) m -,
m = 1-3, and X a is halogen; and
Ar is a 5-10 member aromatic structure containing 0-2 members of the group
consisting of nitrogen, oxygen and sulfur, which is unsubstituted or substituted by
halogen up to per-halo and optionally substituted by Z nl , wherein nl is 0 to 3 and
each Z is independently selected from the group consisting of -CN, -C0 2 R 7 ,
-C(0)NR 7 R\ -C(O)- NR 7 , -N0 2 , -OR 7 , - SR 7 , - NR 7 R 7 , -NR 7 C(0)OR 7 , -C(0)R 7 ,
-NR 7 C(0)R 7 , C r C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 3 -C 13 hetaryl, C 7 -C 24
alkaryl, Q-C^ alkheteroaryl, substituted C r C 10 alkyl, substituted C 3 -C 10 cycloalkyl,
substituted C 7 -C 24 alkaryl and substituted C 4 -C 23 alkheteroaryl; wherein the one or
more substituents of Z is selected from the group consisting of -CN, -C0 2 R 7 ,
-C(0)NR 7 R 7 , -OR 7 , -SR 7 , -N0 2 , -NR 7 R 7 , -NR 7 C(0)R 7 and -NR 7 C(0)OR\
R 4 ' , R 5 'and R 6 are each independently H, halogen, C M0 - alkyl, optionally substituted
by halogen up to perhaloalkyl,
C 1 -Cj 0 alkoxy, optionally substituted by halogen up to perhaloalkoxy or -X-
either one of R 4 ' , R 5 ' or R 6 ' is -X-Y or two adjacent of R 4 ' , R 5 ' and R 6 *
together are a hetaryl ring with 5-12 atoms optionally substituted by C,. 10 alkyl, C,., 0
alkoxy, C 3 . I0 cycloalkyl, C 2 . 10 alkenyl, C W10 alkanoyl, C M2 aryl, C 5 . 12 hetaryl or C^^
ar alkyl;
R 6 ' is additionally -NHCOR 1 , - NR^OR 1 or N0 2 ;
R 1 is C,. 10 alkyl optionally substituted by halogen up to perhalo;
or
Y, and
WO 99/32436
PCT/US98/26081
R 3 ' is independently H, halogen, C wo alkyl, optionally substituted by halogen up
to perhaloalkyl, C M0 alkoxy, optionally substituted by halogen up to
perhaloalkoxy;
X is -CH 2 -, -S-, -N(CH 3 )-, -NHC(O)-, -CH 2 -S-, -C(O)-, or -Os
X is additionally a single bond where Y is pyridyl; and
Y is phenyl, pyridyl, naphthyl, pyridone, pyrazine, pyrimidine, benzodioxane,
benzopyridine or benzothiazole, each optionally substituted by Ci. 10 -alkyl,
Ci^o-alkoxy, halogen, OH, -SCH 3> or N0 2 or, where Y is phenyl, by
-fa
6
or a pharmaceutically acceptable salt thereof .
Preferably, compounds of formula II are of formula Ila:
Ila
wherein
R 3 , R 4 , R 5 and R 6 are each independently H, halogen, N0 2 , C,., 0 - alkyl, optionally
substituted by halogen, up to perhaloalkyl, or C,., 0 -alkoxy, optionally substituted by
halogen, up to perhalo; and one of R 3 -R 6 can be -X-Y; or two adjacent R 3 -R 6 can
together be an aryl or hetaryl ring with 5-12 atoms, optionally substituted by C,. 10 -
alkyl, C,. 10 -alkoxy, C 3 . 10 -cycloalkyl, C 2 . 10 -alkenyl, C,., 0 -alkanoyl; C 6 . 12 -aryl, C 5 ., 2 -
hetaryl, Ce, 12 -alkaryl, halogen; -NR 1 ; -N0 2 ; -CF 3 ; -COOR 1 ; -NHCOR 1 ; -CN;
-CONR'R 1 ; -S0 2 R 2 ; -SOR 2 ; -SR 2 ; in which R 1 is H or C M0 -alkyl, optionally
substituted by halogen, up to perhalo, and R 2 is C^o-alkyl, optionally substituted by
halogen, up to perhalo.
7
WO 99/32436
PCT/US98/26081
In formula I, suitable hetaryl groups B include, but are not limited to, 5-12 carbon-
atom aromatic rings or ring systems containing 1-3 rings, at least one of which is
aromatic, in which one or more, e.g., 1-4 carbon atoms in one or more of the rings can
be replaced by oxygen, nitrogen or sulfur atoms. Each ring typically has 3-7 atoms.
For example, B can be 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-, 2- or 3-
pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4-
or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-,
5- or 6-pyrimidinyl, 1,2,3-triazol-l-, -4- or -5-yl, 1,2,4-triazol-l-, -3- or -5-yl, 1- or 5-
tetrazolyl, l,2,3-oxadiazol-4- or -5-yl, l,2,4-oxadiazol-3- or -5-yl, l,3,4-thiadiazol-2-
or-5-yl, l,2,4-oxadiazol-3- or -5-yl, l,3,4-thiadiazol-2- or -5-yl, l,3,4-thiadiazol-3-
or _5_ y i, l,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-
thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-,
5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-
benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl,
3_ ? 4-, 5. 6- or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or
7-benzisothiazolyl, 2-, 4-, 5-, 6- or 7-benz-l,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-
quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-,
3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, or additionally
optionally substituted phenyl, 2- or 3-thienyl, 1,3,4-thiadiazolyl, 3-pyrryl, 3-pyrazolyl,
2-thiazolyl or 5-thiazolyl, etc. For example, B can be 4-methyl-phenyl, 5-methyl-2-
thienyl, 4-methyl-2-thienyl, l-methyl-3-pyrryl, l-methyl-3-pyrazolyl, 5-methyl-2-
thiazolyl or 5-methyl-l,2,4-thiadiazol-2-yl.
Suitable alkyl groups and alkyl portions of groups, e.g., alkoxy, etc. throughout
include methyl, ethyl, propyl, butyl, etc., including all straight-chain and branched
isomers such as isopropyl, isobutyl, jec-butyl, tert-butyl, etc.
Suitable aryl groups include, for example, phenyl and 1- and 2-naphthyl.
Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclohexyl, etc. The term
" cycloalkyl" , as used herein, refers to cyclic structures with or without alkyl
substitutents such that, for example, "C 4 cycloalkyl" includes methyl substituted
8
WO 99/32436
PCT/US98/26081
cyclopropyl groups as well as cyclobutyl groups. The term "cycloaUeyl" also
includes saturated heterocyclic groups.
Suitable halogen groups include F, CI, Br, and/or I, from one to per-substitution (i.e.,
5 all H atoms on a group replaced by a halogen atom) being possible where an alkyl
group is substituted by halogen, mixed substitution of halogen atom types also being
possible on a given moiety.
The present invention is also directed to pharmaceutically acceptable salts of Formula
10 I. Suitable pharmaceutically acceptable salts are well known to those skilled in the art
and include basic salts of inorganic and organic acids, such as hydrochloric acid,
hydrobromic acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic
acid, sulphonic acid, acetic acid, trifluoroacetic acid, malic acid tartaric acid, citric
acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid,
15 salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically
acceptable salts include acid salts of inorganic bases, such as salts containing alkaline
cations (e.g., Li + Na + or K + ), alkaline earth cations (e.g., Mg +2 , Ca +2 or Ba +2 ), the
ammonium cation, as well as acid salts of organic bases, including aliphatic and
aromatic substituted ammonium, and quaternary ammonium cations such as those
20 arising from protonation or peralkylation of triethylamine, AW-diethylamine, N,N-
dicyclohexylamine, pyridine, ^/,iV-dimethylaminopyridine (DMAP), 1,4-
diazabicyclo[2.2.2]octane (DABCO), l,5-diazabicyclo[4.3.0]non-5-ene (DBN) and
l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
25 A number of the compounds of Formula I possess asymmetric carbons and can
therefore exist in racemic and optically active forms. Methods of separation of
enantiomeric and diastereomeric mixtures are well known to one skilled in the art.
The present invention encompasses any isolated racemic or optically active form of
compounds described in Formula I which possess Raf kinase inhibitory activity.
30
The compounds of Formula I may be prepared by use of known chemical reactions
and procedures. Nevertheless, the following general preparative methods are
presented to aid one of skill in the art in synthesizing the inhibitors, with more
9
WO 99/32436
PCT7US98/26081
detailed examples being presented in the experimental section describing the working
examples.
General Preparative Methods
The compounds of Formula I may be prepared by the use of known chemical
reactions and procedures, some from starting materials which are commercially
available. Nevertheless, general preparative methods are provided below to aid one
skilled in the art in synthesizing these compounds, with more detailed examples being
provided in the experimental section which follows.
Substituted anilines may be generated using standard methods (March. Advanced
Organic Chemistry, 3 rd Ed.; John Wiley: New York (1985). Larock. Comprehensive
Organic Transformations; VCH Publishers: New York (1989)). As shown in Scheme
I, aryl amines are commonly synthesized by reduction of nitroaryls using a metal
catalyst, such as Ni, Pd, or Pt, and H 2 or a hydride transfer agent, such as formate,
cyclohexadiene, or a borohydride (Rylander. Hydrogenation Methods; Academic
Press: London, UK (1985)). Nitroaryls may also be directly reduced using a strong
hydride source, such as LiAlH 4 (Seyden-Penne. Reductions by the Alumino- and
Borohydrides in Organic Synthesis; VCH Publishers: New York (1991)), or using a
zero valent metal, such as Fe, Sn or Ca, often in acidic media. Many methods exist
for the synthesis of nitroaryls (March. Advanced Organic Chemistry, 3 rd Ed.; John
Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH
Publishers: New York (1989)).
H 2 / catalyst
ArN0 2
ArNH 2
(eg. Fe, Sn, Ca)
Scheme I
Reduction of Nitroaryls to Aryl Amines
10
WO 99/32436
PCT/US98/26081
Nitroaryls are commonly formed by electrophilic aromatic nitration using HN0 3 , or
an alternative N0 2 + source. Nitroaryls may be further elaborated prior to reduction.
Thus, nitroaryls substituted with
HN0 3
Ar-H — ► ArNQ 2
potential leaving groups (eg. F, CI, Br, etc.) may undergo substitution reactions on
treatment with nucleophiles, such as thiolate (exemplified in Scheme II) or phenoxide.
Nitroaryls may also undergo Ullman-type coupling reactions (Scheme II).
ArSH
base
<p ^S-Ar
Br— Ar
CuO / base
Scheme II Selected Nucleophilic Aromatic Substitution using Nitroaryls
Nitroaryls may also undergo transition metal mediated cross coupling
reactions. For example, nitroaryl electrophiles, such as nitroaryl bromides, iodides or
triflates, undergo palladium mediated cross coupling reactions with aryl nucleophiles,
such as arylboronic acids (Suzuki reactions, exemplified below), aryltins (Stille
reactions) or arylzincs (Negishi reaction) to afford the biaryl (5).
0 2 N ArB(OR') 2 OsN^^^^
> ► > V-Ar
R ^v=/ Pd(0) r ^a=/
4 5
Either nitroaryls or anilines may be converted into the corresponding arenesulfonyl
chloride (7) on treatment with chlorosulfonic acid. Reaction of the sulfonyl chloride with
a fluoride source, such as KF then affords sulfonyl fluoride (8). Reaction of sulfonyl
fluoride 8 with trimethylsilyl trifluoromethane in the presence of a fluoride source, such as
tris(dimethylamino)sulfonium difluorotrimethylsiliconate (TASF) leads to the
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corresponding trifluoromethylsulfone (9). Alternatively, sulfonyl chloride 7 may be
reduced to the arenethiol (10), for example with zinc amalgum. Reaction of thiol 10 with
CHC1F 2 in the presence of base gives the difluoromethyl mercaptam (11), which may be
oxidized to the sulfone (12) with any of a variety of oxidants, including Cr0 3 -acetic
anhydride (Sedova et al. Zh. Org. Khim. 1970, 6, (568).
so 2 ci
Scheme III Selected Methods of Fluorinated Aryl Sulfone Synthesis
As shown in Scheme IV, non-symmetrical urea formation may involve reaction of an
aryl isocyanate (14) with an aryl amine (13). The heteroaryl isocyanate may be
synthesized from a heteroaiyl amine by treatment with phosgene or a phosgene
equivalent, such as trichloromethyl chloroformate (diphosgene), bis(trichloromethyl)
carbonate (triphosgene), or A/'^'-carbonyldiimidazole (GDI). The isocyanate may
also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an
acid halide or an anhydride by a Curtius-type rearrangement. Thus, reaction of acid
derivative 16 with an azide source, followed by rearrangement affords the isocyanate.
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The corresponding carboxylic acid (17) may also be subjected to Curtius-type
rearrangements using diphenylphosphoryl azide (DPP A) or a similar reagent.
Ar 1 — NH 2 13
COCI 2
t
Ar— NCO ► Ar'^ K1 >k K1 ,Ar
14
N N
H H
15
DPPA
O O
Ar^X Ar 1 ^OH
16 17
Scheme IV Selected Methods of Non-Symmetrical Urea Formation
Finally, ureas may be further manipulated using methods familiar to those
skilled in the art.
The invention also includes pharmaceutical compositions including a compound of
Formula I, and a physiologically acceptable carrier.
10
The compounds may be administered orally, dermally, parenterally, by injection, by
inhalation or spray, or sublingually rectally or vaginally in dosage unit formulations.
The term 'administration by injection' includes intravenous, intraarticular,
intramuscular, subcutaneous and parenteral injections, as well as use of infusion
15 techniques. Dermal administration may include topical application or transdermal
administration. One or more compounds may be present in association with one or
more non-toxic pharmaceutical^ acceptable carriers and if desired other active
ingredients.
20 Compositions intended for oral use may be prepared according to any suitable method
known to the art for the manufacture of pharmaceutical compositions. Such
compositions may contain one or more agents selected from the group consisting of
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diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in
order to provide palatable preparations. Tablets contain the active ingredient in
admixture with non-toxic pharmaceutically acceptable excipients which are suitable
for the manufacture of tablets. These excipients may be, for example, inert diluents,
such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium
phosphate; granulating and disintegrating agents, for example, corn starch, or alginic
acid; and binding agents, for example magnesium stearate, stearic acid or talc. The
tablets may be uncoated or they may be coated by known techniques to delay
disintegration and adsorption in the gastrointestinal tract and thereby provide a
sustained action over a longer period. For example, a time delay material such as
glyceryl monostearate or glyceryl distearate may be employed. These compounds
may also be prepared in solid, rapidly released form.
Formulations for oral use may also be presented as hard gelatin capsules wherein the
active ingredient is mixed with an inert solid diluent, for example, calcium carbonate,
calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient
is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive
oil-
Aqueous suspensions containing the active materials in admixture with excipients
suitable for the manufacture of aqueous suspensions may also be used. Such
excipients are suspending agents, for example sodium carboxymethylcellulose,
methylcellulose, hydroxypropyl-methylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents
may be a naturally-occurring phosphatide, for example, lecithin, or condensation
products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate,
or condensation products of ethylene oxide with long chain aliphatic alcohols, for
example heptadecaethylene oxycetanol, or condensation products of ethylene oxide
with partial esters derived from fatty acids and hexitol such as polyoxyethylene
sorbitol monooleate, or condensation products of ethylene oxide with partial esters
derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan
monooleate. The aqueous suspensions may also contain one or more preservatives,
for example ethyl, or «-propyl /?-hydroxybenzoate, one or more coloring agents, one
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or more flavoring agents, and one or more sweetening agents, such as sucrose or
saccharin.
Dispersible powders and granules suitable for preparation of an aqueous suspension
by the addition of water provide the active ingredient in admixture with a dispersing
or wetting agent, suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those already mentioned
above. Additional excipients, for example, sweetening, flavoring and coloring agents,
may also be present.
The compounds may also be in the form of non-aqueous liquid formulations, e.g., oily
suspensions which may be formulated by suspending the active ingredients in a
vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a
mineral oil such as liquid paraffin. The oily suspensions may contain a thickening
agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such
as those set forth above, and flavoring agents may be added to provide palatable oral
preparations. These compositions may be preserved by the addition of an anti-oxidant
such as ascorbic acid.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water
emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil,
or a mineral oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents may be naturally-occurring gums, for example gum acacia or gum
tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and
esters or partial esters derived from fatty acids and hexitol anhydrides, for example
sorbitan monooleate, and condensation products of the said partial esters with
ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions
may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol,
propylene glycol, sorbitol or sucrose. Such formulations may also contain a
demulcent, a preservative and flavoring and coloring agents.
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The compounds may also be administered in the form of suppositories for rectal or
vaginal administration of the drug. These compositions can be prepared by mixing
the drug with a suitable non-irritating excipient which is solid at ordinary
temperatures but liquid at the rectal temperature or vaginal temperature and will
therefore melt in the rectum or vagina to release the drug. Such materials include
cocoa butter and polyethylene glycols.
Compounds of the invention may also be administrated transdermally using methods
known to those skilled in the art (see, for example: Chien; " Transdermal Controlled
Systemic Medications"; Marcel Dekker, Inc.; 1987. Lipp et al. WO94/04157
3Mar94). For example, a solution or suspension of a compound of Formula I in a
suitable volatile solvent optionally containing penetration enhancing agents can be
combined with additional additives known to those skilled in the art, such as matrix
materials and bactericides. After sterilization, the resulting mixture can be
formulated following known procedures into dosage forms. In addition, on treatment
with emulsifying agents and water, a solution or suspension of a compound of
Formula I may be formulated into a lotion or salve.
Suitable solvents for processing transdermal delivery systems are known to those
skilled in the art, and include lower alcohols such as ethanol or isopropyl alcohol,
lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate,
polar ethers such as tetrahydrofuran, lower hydrocarbons such as hexane, cyclohexane
or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform,
trichlorotrifluoroethane, or trichlorofluoroethane. Suitable solvents may also include
mixtures of one or more materials selected from lower alcohols, lower ketones, lower
carboxylic acid esters, polar ethers, lower hydrocarbons, halogenated hydrocarbons.
Suitable penetration enhancing materials for transdermal delivery system are known
to those skilled in the art, and include, for example, monohydroxy or polyhydroxy
alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated
C 8 -C 18 fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated
C 8 -C 18 fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to
24 carbons such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl,
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tertbutyl or monoglycerin esters of acetic acid, capronic acid, lauric acid, myristinic
acid, stearic acid, or palmitic acid, or diesters of saturated or unsaturated dicarboxylic
acids with a total of up to 24 carbons such as diisopropyl adipate, diisobutyl adipate,
diisopropyl sebacate, diisopropyl maleate, or diisopropyl fumarate. Additional
penetration enhancing materials include phosphatidyl derivatives such as lecithin or
cephalin, terpenes, amides, ketones, ureas and their derivatives, and ethers such as
dimethyl isosorbid and diethyleneglycol monoethyl ether. Suitable penetration
enhancing formulations may also include mixtures of one or more materials selected
from monohydroxy or polyhydroxy alcohols, saturated or unsaturated C 8 -Ci 8 fatty
alcohols, saturated or unsaturated C 8 -C 18 fatty acids, saturated or unsaturated fatty
esters with up to 24 carbons, diesters of saturated or unsaturated discarboxylic acids
with a total of up to 24 carbons, phosphatidyl derivatives, terpenes, amides, ketones,
ureas and their derivatives, and ethers.
Suitable binding materials for transdermal delivery systems are known to those skilled
in the art and include polyacrylates, silicones, polyurethanes, block polymers,
styrenebutadiene copolymers, and natural and synthetic rubbers. Cellulose ethers,
derivatized polyethylenes, and silicates may also be used as matrix components.
Additional additives, such as viscous resins or oils may be added to increase the
viscosity of the matrix.
For all regimens of use disclosed herein for compounds of Formula I, the daily oral
dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The
daily dosage for administration by injection, including intravenous, intramuscular,
subcutaneous and parenteral injections, and use of infusion techniques will preferably
be from 0.01 to 200 mg/Kg of total body weight. The daily vaginal dosage regime
will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily topical
dosage regimen will preferably be from 0.1 to 200 mg administered between one to
four times daily. The transdermal concentration will preferably be that required to
maintain a daily does of from 0.01 to 200 mg/Kg. The daily inhalation dosage
regimen will preferably be from 0.01 to 10 mg/Kg of total body weight.
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It will be appreciated by those skilled in the art that the particular method of
administration will depend on a variety of factors, all of which are considered
routinely when administering therapeutics. It will also be understood, however, that
the specific dose level for any given patient will depend upon a variety of factors,
including, the activity of the specific compound employed, the age of the patient, the
body weight of the patient, the general health of the patient, the gender of the patient,
the diet of the patient, time of administration, route of administration, rate of
excretion, drug combinations, and the severity of the condition undergoing therapy. It
will be further appreciated by one skilled in the art that the optimal course of
treatment, i.e., the mode of treatment and the daily number of doses of a compound of
Formula I or a pharmaceutically acceptable salt thereof given for a defined number of
days, can be ascertained by those skilled in the art using conventional treatment tests.
The compounds of Figure I are producible from known compounds (or from starting
materials which, in turn, are producible from known compounds), e.g., through the
general preparative methods shown above. The activity of a given compound to
inhibit raf kinase can be routinely assayed, e.g., according to procedures disclosed
below. The following examples are for illustrative purposes only and are not
intended, nor should they be construed to limit the invention in any way.
The entire disclosure of all applications, patents and publications cited above and
below, are hereby incorporated by reference, including provisional application
(Attorney Docket Number Bayer 6 VI), filed on December 22, 1997, as SN
08/996,344 and converted on December 22, 1998.
EXAMPLES
All reactions were performed in flame-dried or oven-dried glassware under a positive
pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise
indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and
introduced into reaction vessels through rubber septa. Unless otherwise stated, the
term 'concentration under reduced pressure' refers to use of a Buchi rotary evaporator
at approximately 15 mmHg.
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All temperatures are reported uncorrected in degrees Celsius (°C). Unless otherwise
indicated, all parts and percentages are by weight.
Commercial grade reagents and solvents were used without further purification. Thin-
layer chromatography (TLC) was performed using Whatman® pre-coated glass-backed
silica gel 60A F-254 250 urn plates. Visualization of plates was effected by one or
more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine
vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in
ethanol followed by heating, (d) immersion of the plate in a cerium sulfate solution
followed by heating, and/or (e) immersion of the plate in an acidic ethanol solution of
2,4-dinitrophenylhydrazine followed by heating. Column chromatography (flash
chromatography) was performed using 230-400 mesh EM Science® silica gel.
Melting points (mp) were determined using a Thomas-Hoover melting point apparatus
or a Mettler FP66 automated melting point apparatus and are uncorrected. Fourier
transform infrared sprectra were obtained using a Mattson 4020 Galaxy Series
spectrophotometer. Proton ('H) nuclear magnetic resonance (NMR) spectra were
measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either
Me 4 Si (d 0.00) or residual protonated solvent (CHC1 3 6 7.26; MeOH 8 3.30; DMSO 8
2.49) as standard. Carbon ( ,3 C) NMR spectra were measured with a General Electric
GN-Omega 300 (75 MHz) spectrometer with solvent (CDC1 3 8 77.0; MeOD-d 3 ; 8
49.0; DMSO-d 6 8 39.5) as standard. Low resolution mass spectra (MS) and high
resolution mass spectra (HRMS) were either obtained as electron impact (EI) mass
spectra or as fast atom bombardment (FAB) mass spectra. Electron impact mass
spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass spectrometer
equipped with a Vacumetrics Desorption Chemical Ionization Probe for sample
introduction. The ion source was maintained at 250 °C. Electron impact ionization
was performed with electron energy of 70 eV and a trap current of 300 uA. Liquid-
cesium secondary ion mass spectra (FAB-MS), an updated version of fast atom
bombardment were obtained using a Kratos Concept 1-H spectrometer. Chemical
ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS-Engine
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(5989A) with methane or ammonia as the reagent gas (lxl 0" 4 torr to 2.5x1 0" 4 torr).
The direct insertion desorption chemical ionization (DCI) probe (V accumetrics, Inc.)
was ramped from 0-1.5 amps in 10 sec and held at 10 amps until all traces of the
sample disappeared ( -1-2 min). Spectra were scanned from 50-800 amu at 2 sec per
scan. HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using a
Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable
wavelength detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer
with electrospray ionization. Spectra were scanned from 120-800 amu using a
variable ion time according to the number of ions in the source. Gas chromatography
- ion selective mass spectra (GC-MS) were obtained with a Hewlett Packard 5890 gas
chromatograph equipped with an HP-1 methyl silicone column (0.33 mM coating; 25
m x 0.2 mm) and a Hewlett Packard 5971 Mass Selective Detector (ionization energy
70 eV). Elemental analyses are conducted by Robertson Microlit Labs, Madison NJ.
All compounds displayed NMR spectra, LRMS and either elemental analysis or
HRMS consistant with assigned structures.
List of Abbreviations and Acronyms:
AcOH acetic acid
anh anhydrous
BOC terf-butoxycarbonyl
cone concentrated
dec decomposition
DMPU 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone
DMF TViiV-dimethylformamide
DMSO dimethylsulfoxide
DPP A diphenylphosphoryl azide
EtOAc ethyl acetate
EtOH ethanol (100%)
Et 2 0 diethyl ether
Et 3 N triethylamine
w-CPBA 3-chloroperoxybenzoic acid
MeOH methanol
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pet. ether petroleum ether (boiling range 30-60 °C)
THF tetrahydrofuran
TFA trifluoroacetic acid
Tf trifluoromethanesulfonyl
A, General Methods for Synthesis of Substituted Anilines
Al. Synthesis of 2,5-Dioxopyrrolidinylanilines
Step 1. 4-terr-Butyl-l-(2,S-dioxo-l-pyrroIidinyl)-2-nitrobenzene: To a solution of
4-terMDutyl-2-nitroaniline (1.04 g, 5.35 mmol) in xylene (25 mL) was added succinic
anhydride (0.0535 g, 5.35 mmol) and triethylamine (0.75 mL, 5.35 mmol). The
reaction mixture was heated at the reflux temp, for 24 h, cooled to room temp, and
diluted with Et 2 0 (25 mL). The resulting mixture was sequentially washed with a
10% HC1 solution (50 mL), a saturated NH 4 C1 solution (50 mL) and a saturated NaCl
solution (50 mL), dried (MgS0 4 ), and concentrated under reduced pressure. The
residue was purified by flash cromatography (60% EtOAc/40% hexane) to yield the
succinimide as a yellow solid (1.2 g, 86%): mp 135-138 °C; 'H NMR (CHC1 3 ) 5 1.38
(s, 9H), 2.94-2.96 (m, 4H), 7.29-7.31 (m, 1H), 7.74-7.78 (m, 1H), 8.18-8.19 (m, 1H).
Step 2. 5-terr-Butyl-2-(2,5-dioxo-l-pyrrolidinyl)aniline: To a solution of
butyl-l-(2,5-dioxo-l-pyrrolidinyl)-2-nitrobenzene (1.1 g, 4.2 mmol) in EtOAc (25
mL) was added a 10% Pd/C (0.1 g). The resulting slurry was placed under a H 2
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atmosphere using 3 cycles of an evacuate-quench protocol and was allowed to stir
under a H 2 atmosphere for 8 h. The reaction mixture was filtered through a pad of
Celite® and the residue was washed with CHC1 3 . The combined filtrate was
concentrated under reduced pressure to yield the desired aniline as an off-white solid
(0.75 g, 78%): mp 208-211 °C; 'H-NMR (DMSO-d 6 ) 8 1.23 (s, 9H), 2.62-2.76 (m,
4H), 5.10 (br s, 2H), 6.52-6,56 (m, 1H), 6.67-6.70 (m, 2H).
A2. General Method for the Synthesis of Tetrahydrofuranyloxyanilines
Step 1.4-ter*-Butyl-l-(3-tetrahydrofuranyIoxy)-2-nitrobenzene: To a solution of 4-
tert-butyl-2-nitrophenol (1.05 g, 5.4 mmol) in anh THF (25 mL) was added 3-
hydroxytetrahydrofuran (0.47 g, 5.4 mmol) and triphenylphosphine (1.55 g, 5.9
mmol) followed by diethyl azodicarboxylate (0.93 ml, 5.9 mmol) and the mixture was
allowed to stir at room temp, for 4 h. The resulting mixture was diluted with Et 2 0 (50
mL) and washed with a saturated NH 4 C1 solution (50 mL) and a saturated NaCl
solution (50 mL), dried (MgS0 4 ), and concentrated under reduced pressure. The
residue was purified by flash cromatography (30% EtOAc/70% hexane) to yield the
desired ether as a yellow solid (1.3 g, 91%): 'H-NMR (CHC1 3 ) 6 1.30 (s, 9H), 2.18-
2.24 (m, 2H), 3.91-4.09 (m, 4H), 5.00-5.02 (m, 1H), 6.93 (d, J=8.8 Hz, 1H), 7.52 (dd,
J=2.6, 8.8 Hz, 1H), 7.81 (d, J=2.6 Hz, 1H).
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Step2.5-^r/-Butyl-2-(3-tetrahydrofuranyloxy)aniIine: To a solution of 4-tert-
butyl- l-(3-tetrahydrofuranyloxy)-2-nitrobenzene (LI 7 g, 4.4 mmol) in EtOAc (25
mL) was added 10% Pd/C (0.1). The resulting slurry was placed under a H 2
atmosphere using 3 cycles of an evacuate-quench protocol and was allowed to stir
under a H 2 atmosphere for 8 h. The reaction mixture was filtered through a pad of
Celite® and washed with CHC1 3 . The combined filtrate was concentrated under
reduced pressure to yield of the desired aniline as a yellow solid (0.89 g, 86%): mp
79-82 °C; 'H-NMR (CHC1 3 ) 5 1.30 (s, 9H), 2.16-2.20 (m, 2H), 3.78 (br s, 2H), 3.85-
4.10 (m, 4H),4.90 (m, 1H), 6.65-6.82 (m, 3H).
A3* General Method for the Synthesis of Trifluoromethanesulfonylanilines
SQ 2 F
Step 1. 2-Methoxy-5-(fluorosulfonyl)acetanilide: Acetic anhydride (0.90 mL, 9.6
mmol) was added to a solution of 4-methoxymetanilyl fluoride (1.0 g, 4.8 mmol) in
pyridine (15 mL). After being stirred at room temp, for 4 h, the reaction mixture was
concentrated under reduced pressure. The resulting residue was dissolved in CH 2 C1 2
(25 mL), washed with a saturated NaHC0 3 solution (25 mL), dried (Na^OJ, and
concentrated under reduced pressure to give a foam which was triturated with a
Et 2 0/hexane solution to provide the title compound (0.85 g): *H-NMR (CDC1 3 ) 8
2.13 (s, 3H), 3.98 (s, 3H), 7.36 (d, .7=8.5 Hz, 1H), 7.82 (dd, J=2.6, 8.8 Hz, 1H), 8.79
(d, J=2.2 Hz, 1H), 9.62 (br s, 1H).
suspension of tris(dimethylamino)sulfonium difluorotrimethylsiliconate (0.094 g, 0.34
mmol) in THF (4 mL) was added a solution of (trifluoromethyl)trimethylsilane (1.0
mL, 6.88 mmol) in THF (3 mL) followed by a solution of 2-methoxy-5-
(fluorosulfonyl)acetanilide (0.85 g, 3.44 mmol) in THF (3 mL). The reaction mixture
was stirred for 2 h on an ice bath, then was allowed to warm to room temp, and was
MeO
MeO
Step 2.2-Methoxy-5-(trifluoromethanesulfonyl)acetanilide: To an ice-cooled
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then concentrated under reduced pressure. The resulting residue was dissolved in
CH 2 C1 2 (25 mL), washed with water (25 mL), dried (Na^OJ, and concentrated under
reduced pressure. The resulting material was purified by flash chromatography (3%
MeOH/97% CH 2 C1 2 ) to provide the title compound as a white solid (0.62 g): 'H-NMR
(CDC1 3 ) 5 2.13 (s, 3H) 4.00 (s, 3H), 7.42 (d, J=8.8 Hz, 1H), 7.81 (dd, 7=2.6, 8.8 Hz,
1H), 8.80 (d, J=2.2 Hz, 1H), 9.64 (br s, 1H); FAB-MS m/z 298 ((M+l) + ).
Step 3.2-Methoxy-5-(trifluoromethanesulfonyl)aniline: A solution of 2-methoxy-
5-(trifluoromethanesulfonyl)acetanilide (0.517 g, 1.74 mmol) in EtOH (5 mL) and a 1
N HC1 solution (5 mL) was heated at the reflux temp, for 4 h and the resulting mixture
was concentrated under reduced pressure. The residue was dissolved in CH 2 C1 2 (30
mL), washed with water (30 mL), dried (Na^OJ, and concentrated under reduced
pressure to afford the title compound as a gum (0.33 g): 'H-NMR (CDC1 3 ) 5 3.90 (s,
3H) 5.57 (br s, 2H), 7.11-7.27 (m, 3H); FAB-MS m/z 256 ((M+l) + ). This material
was used in urea formation without further purification.
General Method for Aryl Amine Formation via Phenol Nitration Followed by
Ether Formation and Reduction
Step 1. 2-Nitro-5-terf-butylphenol : A mixture of fuming nitric acid (3.24 g, 77.1
mmol) in glacial HO Ac (10 mL) was added drop wise to a solution of m-tert-
butylphenol (11.58 g, 77.1 mmol) in glacial HOAc (15 mL) at 0 °C. The mixture was
allowed to stir at 0 °C for 15 min then warmed to room temp. After 1 h the mixture
was poured into ice water (100 mL) and extracted with E^O (2 x 50 mL). The organic
layer was washed with a saturated NaCl solution (100 mL), dried (MgS0 4 ) and
concentrated in vacuo. The residue was purified by flash chromatography (30%
EtO Ac/70% hexane) to give the desired phenol (4.60 g, 31%): 'H-NMR (DMSO-d 6 ) 8
MeO
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1.23 (s, 9H), 7.00 (dd, 7=1.84, 8.83 Hz, 1H), 7.07 (d, .7=1.84 Hz, 1H), 7.82 (d, 7=8.83
Hz, 1H), 10.74 (s, 1H).
OMe
Step 2. 2-Nitro-5-terf-butylanisole: A slurry of 2-nitro-5-terr-butylphenol (3.68 g,
5 18.9 mmol) and K 2 C0 3 (3.26 g, 23.6 rnmol) in anh DMF (100 mL) was stirred at
room temp with stirring for 15 min then treated with iodomethane (2.80 g, 19.8 mmol)
via syringe. The reaction was allowed to stir at room temp for 1 8 h., then was treated
with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic
layers were washed with a saturated NaCl solution (50 mL), dried (MgS0 4 ) and
10 concentrated in vacuo to give the desired ether (3.95 g, 100%): 'H-NMR (DMSO-d 6 )
5 1.29 (s, 9H), 3.92 (s, 3H), 7.10 (dd, 7=1.84, 8.46 Hz, 1H), 7.22 (d, 7=1.84 Hz, 1H),
7.79 (d, 7=8.46 Hz, 1H). This material was used in the next step without further
purification.
OMe
15 Step 3. 4-terf-Butyl-2-methoxyaniIine: A solution of 2-mtro-5-*ert-butylanisole
(3.95 g, 18.9 mmol) in MeOH (65 mL) and added to a flask containing 10% Pd/C in
MeOH (0.400 g), then placed under a H 2 atmosphere (balloon). The reaction was
allowed to stir for 18 h at room temp, then filtered through a pad of Celite® and
concentrated in vacuo to afford the desired product as a dark sitcky solid (3.40 g,
20 99%): 'H-NMR (DMSO-cLj 8 1.20 (s, 9H), 3.72 (s, 3H), 4.43 (br s, 2H), 6.51 (d,
7=8.09 Hz, 1H), 6.64 (dd, 7=2.21, 8.09 Hz, 1H), 6.76 (d, 7=2.21 Hz, 1H).
A5. General Method for Aryl Amine Formation via Carboxylic Acid Esterification
Followed by Reduction
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Step 1 . Methyl 2-Nitro-4-(trifluoromethyl)benzoate: To a solution of 2-nitro-4-
(trifluoromethyl)benzoic acid (4.0 g, 17.0 mmol) in MeOH (150 mL) at room temp
was added cone H 2 S0 4 (2.5 mL). The mixture was heated at the reflux temp for 24 h.,
5 cooled to room temp and concentrated in vacuo. The residue was diluted with water
(100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were
washed with a saturated NaCl solution, dried (MgSOJ, concentrated in vacuo. The
residue was purified by flash chromatography (14% EtOAc/86% hexane) to give the
desired ester as a pale yellow oil (4.17 g, 98%): 'H-NMR (DMSO-d 6 ) 8 3.87 (s, 3H),
10 8.09 (d, 7=7.72 Hz, 1H), 8.25 (dd, 7=1.11, 8.09 Hz, 1H), 8.48 (d, 7=1.11 Hz, 1H).
Step 2 . Methyl 2-Amino-4-(trifluoromethyl)benzoate: A solution of methyl 2-nitro-
4-(trifluoromethyl)benzoate (3.90 g, 15.7 mmol) in EtOAc (100 mL) and added to a
flask containing 10% Pd/C (0.400 mg) in EtOAc (10 mL), then placed under a H 2
15 atmosphere (balloon). The reaction was allowed to stir for 18 h at room temp, then
was filtered through Celite® and concentrated in vacuo to afford the desired product as
a white crystalline solid (3.20 g, 93%): 'H-NMR (DMSO-d 6 ) 5 3.79 (s, 3H), 6.75 (dd,
7=1.84, 8.46 Hz, 1H), 6.96 (br s, 2H), 7.11 (d, 7=0.73 Hz, 1H), 7.83 (d, 7=8.09 Hz,
1H).
20
A6. General Method for Aryl Amine Formation via Ether Formation Followed Ester
Saponification, Curtius Rearrangement, and Carbamate Deprotection
C0 2 Me
OMe
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Step 1. Methyl 3-Methoxy-2-naphttaoate: A slurry of methyl 3-hydroxy-2-
naphthoate (10.1 g, 50.1 mmol) and K 2 C0 3 (7.96 g, 57.6 mmol) in DMF (200 mL)
was stirred at room temp for 15 min, then treated with iodomethane (3.43 mL, 55.1
mmol). The mixture was allowed to stir at room temp overnight, then was treated
with water (200 mL). The resulting mixture was extracted with EtOAc (2 x 200 mL).
The combined organic layers were washed with a saturated NaCl solution (100 mL),
dried (MgS0 4 ), concentrated in vacuo (approximately 0.4 mmHg overnight) to give
the desired ether as an amber oil (10.30 g): 'H-NMR (DMSO-d 6 ) 6 2.70 (s, 3H), 2.85
(s, 3H), 7.38 (app t, .7=8.09 Hz, 1H), 7.44 (s, 1H), 7.53 (app t, J=8.09 Hz, 1H), 7.84
(d, J=8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H).
Step 2. 3-Methoxy-2-naphthoic Acid: A solution of methyl 3-methoxy-2-
naphthoate (6.28 g, 29.10 mmol) and water (10 mL) in MeOH (100 mL) at room temp
was treated with a 1 N NaOH solution (33.4 mL, 33.4 mmol). The mixture was heated
at the reflux temp for 3 h, cooling to room temp, and made acidic with a 10% citric
acid solution. The resulting solution was extracted with EtOAc (2 x 100 mL). The
combined organic layers were washed with a saturated NaCl solution, dried (MgS0 4 )
and concentrated in vacuo. The residue was triturated with hexanes and washed
several times with hexanes to give the desired carboxylic acid as a white crystalline
solid (5.40 g, 92%): 'H-NMR (DMSO-d 6 ) 8 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54
(m, 1H), 7.83 (d, J-8.09 Hz, 1H), 7.91 (d, J=8.09 Hz, 1H), 8.19 (s, 1H), 12.83 (br s,
1H).
Step 3. 2-(iV-(Carbobenzyloxy)amino-3-methoxynaphthalene: A solution of 3-
methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and Et 3 N (2.59 mL, 18.6 mmol) in anh
toluene (70 mL) was stirred at room temp, for 15 min., then treated with a solution of
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diphenylphosphoryl azide (5.12 g, 18.6 mmol) in toluene (10 mL) via pipette. The
resulting mixture was heated at 80 °C for 2 h. After cooling the mixture to room temp,
benzyl alcohol (2.06 mL, 20 mmol) was added via syringe. The mixture was then
warmed to 80 °C overnight. The resulting mixture was cooled to room temp.,
5 quenched with a 10% citric acid solution, and extracted with EtOAc (2 x 100 mL).
The combined organic layers were washed with a saturated NaCl solution, dried
(MgS0 4 ), and concentrated in vacuo. The residue was purified by flash
chromatography (14% EtOAc/86% hexane) to give the benzyl carbamate as a pale
yellow oil (5.1 g, 100%): 'H-NMR (DMSO-d 6 ) 8 3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44
10 (m, 8H), 7.72-7.75 (m, 2H), 8.20 (s, 1H), 8.76 (s, 1H).
Step 4.2-Amino-3-methoxynaphthalene: A slurry of 2-(A^(carbobenzyloxy)amino-
3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10% Pd/C (0.5 g) in EtOAc (70mL)
was maintained under a H 2 atmospheric (balloon) at room temp, overnight. The
1 5 resulting mixture was filtered through Celite® and concentrated in vacuo to give the
desired amine as a pale pink powder (2.40 g, 85%): 'H-NMR (DMSO-d 6 ) 5 3.86 (s,
3H), 6.86 (s, 2H), 7.04-7.16 (m, 2H), 7.43 (d, .7=8.0 Hz, 1H), 7.56 (d, J-8.0 Hz, 1H);
EI-MS m/z 173 (M + ).
2A7. General Method for the Synthesis of Aryl Amines via Metal-Mediated Cross
Coupling Followed by Reduction
OTf
Step 1.5-^-ButyI-2-(trifluoromethanesulfonyl)oxy-l-nitrobenzene: To an ice
cold solution of 4-ter^butyl-2-mtrophenol (6.14 g, 31.5 mmol) and pyridine (10 mL,
25 125 mmol) in CH 2 C1 2 (50 mL) was slowly added trifluoromethanesulfonic anhydride
(10 g, 35.5 mmol) via syringe. The reaction mixture was stirred for 15 min, then
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allowed to warm up to room temp, and diluted with CH 2 C1 2 (100 mL). The resulting
mixture was sequentially washed with a 1M NaOH solution (3 x 100 mL), and a 1M
HC1 solution (3 x 100 mL), dried (MgS0 4 ), and concentrated under reduced pressure
to afford the title compound (8.68 g, 84%): ^-NMR (CDC1 3 ) 8 1.39 (s, 9H), 7.30-
8.20 (m, 3H).
Step 2. 5-terf-Butyl-2-(3-fluorophenyl)-l -nitrobenzene: A mixture of 3-
fluorobenzeneboronic acid (3.80 g, 27.5 mmol), KBr (2.43 g, 20.4 mmol), K 3 P0 4 (6.1
g, 28.8 mmol), and Pd(PPh 3 ) 4 (1.0 g, 0.9 mmol) was added to a solution of 5-tert-
butyl-2-(trifluoromethanesulfonyl)oxy-l -nitrobenzene (6.0 g, 18.4 mmol) in dioxane
(100 mL). The reaction mixture was heated at 80 °C for 24 h, at which time TLC
indicated complete reaction. The reaction mixture was treated with a saturated NH 4 C1
solution (50 mL) and extracted EtOAc (3 x 100 mL). The combined organic layers
were dried (MgS0 4 ) and concentrated under reduced pressure. The residue was
purified by flash chromatography (3% EtOAc/97% hexane) to give the title compound
(4.07 g, 81%): 'H-NMR (CDC1 3 ) 8 1.40 (s, 9H), 6.90-7.90 (m, 7H).
Step 3.5-/^-Butyl-2-(3-fluorophenyI)aniIine: To a solution of 5-ter*-butyl-2-(3-
fluorophenyl)-l -nitrobenzene (3.5 g, 12.8 mmol) and EtOH (24 mL) in EtOAc (96
mL) was added 5% Pd/C (0.350 g) and the resulting slurry was stirred under a H 2
atmosphere for 24 h, at which time TLC indicated complete consumption of starting
material. The reaction mixture was filtered through a pad of Celite® to give the
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desired product (2.2 g, 72%): 'H-NMR (CDC1 3 ) 5 1.35 (s, 9H), 3.80 (br s, 2H), 6.90-
7.50 (m, 7H).
A8. General Method for the Synthesis of Nitroanilines
H 2 N H
Step 1.4-(4-(2-Propoxycarbonylamino)phenyl)methylaniline: A solution of di-tert-
butyl dicarbonate (2.0 g, 9.2 mmol) and 4,4'-methylenedianiline (1.8g, 9.2 mmol) in
DMF (100 mL) was heated at the reflux temp, for 2 h, then cooled to room temp.
This mixture was diluted with EtOAc (200 mL) sequentially washed with a saturated
NH 4 C1 (200 mL) and a saturated NaCl solution (100 mL), and dried (MgSOJ. The
residue was purified by flash chromatography (30% EtOAc/70% hexane) to give the
desired carbamate (1.3 g, 48%): 'H-NMR (CDC1 3 ) 8 1.51 (s, 9H), 3.82 (s, 2H), 6.60-
7.20 (m, 8H).
O z N
Step 2.4-(4-(2-Propoxycarbonylamino)phenyI)methyl-l-nitrobenzene: To an ice
cold solution of 4-(4-(2-propoxycarbonylamino)phenyl)methylaniline (1.05 g, 3.5
mmol) in CH 2 C1 2 (15 mL) was added m-CPBA (1.2 g, 7.0 mmol). The reaction
mixture was slowly allowed to warm to room temp, and was stirred for 45 min, at
which time TLC indicated disappearance of starting material. The resulting mixture
was diluted with EtOAc (50 mL), sequentially washed with a 1M NaOH solution (50
mL) and a saturated NaCl solution (50 mL), and dried (MgS0 4 ). The residue was
purified by flash chromatography (20% EtOAc/80% hexane) to give the desired
nitrobenzene (0.920 g): FAB-MS m/z 328 (M+).
0 2 N
Step 3.4-(4-Nitrophenyl)methylaniline: To a solution of 4-(4-(2-
propoxycarbonylamino)phenyl)methyl-l -nitrobenzene (0.920 g, 2.8 mmol) in dioxane
(10 mL) was added a cone. HC1 solution (4.0 mL) and the resulting mixture was
heated at 80 °C for 1 h at which time TLC indicated disappearance of starting
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material. The reaction mixture was cooled to room temp. The resulting mixture was
diluted with EtOAc (50 mL), then washed with a 1M NaOH solution (3 x 50 mL), and
dried (MgS0 4 ) to give the desired aniline (0.570 mg, 89%): 'H-NMR (CDC1 3 ) 8 3.70
(br s, 2H), 3.97 (s, 2H), 6.65 (d, .7=8.5 Hz, 2H), 6.95 (d, .7=8.5 Hz, 2H), 7.32 (d, .7=8.8
Hz, 2H), 8.10 (d, 7=8.8 Hz, 2H).
General Method for Synthesis of Aryl Anilines via Alkylation of a Nitrophenol
Followed by Reduction
O
r^N^ — Br
Step 1.4-(a-Bromoacetyl)morpholine: To an ice cold solution of morpholine (2.17
g, 24.9 mmol) and diisopropylethylamine (3.21 g, 24.9 mmol) in CH 2 C1 2 (70 mL) was
added a solution of bromoacetyl bromide (5.05 g, 25 mmole) in CH 2 C1 2 (8 mL) via
syringe. The resulting solution was kept at 0 °C for 45 min, then was allowed to
warm to room temp. The reaction mixture was diluted with EtOAc (500 mL),
sequentially washed with a 1M HC1 solution (250 mL) and a saturated NaCl solution
(250 mL), and dried (MgS0 4 ) to give the desired product (3.2 g, 62%): 'H-NMR
(DMSO-d 6 ) 8 3.40-3.50 (m, 4H), 3.50-3.60 (m, 4H), 4.11 (s, 2H).
Step 2.2-(^V-Morpholinylcarbonyl)methoxy-5-terr-butyl-l-nitrobenzene: A slurry
of 4-rert-butyl-2-nitrophenol (3.9 g, 20 mmol) and K 2 C0 3 (3.31 g, 24 mmol) in DMF
(75 mL) was stirred at room temp, for 15 minutes, then a solution of 4-(o>
bromoacetyl)morpholine (4.16 g, 20 mmol) in DMF (10 mL) was added. The reaction
was allowed to stir at room temp, overnight, then was diluted with EtOAc (500 mL)
and sequentially washed with a saturated NaCl solution (4 x 200 mL) and a 1M NaOH
solution (400 mL). The residue was purified by flash chromatography (75%
EtOAc/25% hexane) to give the nitrobenzene (2.13 g, 33%): 'H-NMR (DMSO-d 6 ) 8
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1.25 (s, 9H), 3.35-3.45 (m, 4H), 3.50-3.58 (m, 4H), 5.00 (s, 2H), 7.12 (d, J=8.8 Hz,
1H), 7.50-7.80 (m, 2H).
Step 3. 2-(iV-Morpholinylcarbonyl)methoxy-5-fert-butylaniline: To a solution of 2-
5 (7^-morpholinylcarbonyl)methoxy-5-rert-butyl-l-nitrobenzene(2.13 g, 6.6 mmol) and
EtOH (10 mL) in EtOAc (40 mL) was added 5% Pd/C (0.215 g). The resulting slurry
was stirred under a H 2 atmosphere for 6 h, at which time TLC indicated complete
consumption of starting material. The reaction mixture was filtered through a pad of
Celite® to give the desired product (1.9 g, 98%): 'H-NMR (DMSO-d 6 ) 5 1.18 (s, 9H),
10 3.40-3.50 (m, 4H), 3.50-3.60 (m, 4H), 4.67 (br s, 2H), 4.69 (s, 2H), 6.40-6.70 (m, 3H).
A10. General Method for Aryl Amine Formation via Nitrophenol Alkylation Followed
by Reduction
NO-
15 Step 1.5-tert-Butyl-2-(2-hydroxyethoxy)-l-nitrobenzene: A solution of A-tert-
butyl-2-nitrophenol (30 g, 0.15 mol) and tetra-n-butylammonium fluoride (0.771 g,
3.0 mmol) in ethylene carbonate (10.24 mL. 0.15 mol) was heated at 150 °C for 18 h,
then cooled to room temp, and separated between water (50 mL) and CH 2 C1 2 (50 mL).
The organic layer was dried (MgS0 4 ) and concentrated under reduced pressure. The
20 residue was purified by column chromatography (20% EtOAc/80% hexane) to afford
the desired product as a brown oil (35.1 g, 90%): 'H-NMR (DMSO-d*) 8 1.25 (s, 9H),
3.66-3.69 (m, 2H), 4.10-4.14 (t, J=5.0 Hz, 2H), 4.85 (t, .7=5.0 Hz, 1H), 7.27 (d, .7=8.8
Hz, 1H), 7.60-7.64 (m, 1H), 7.75 (d, .7=2.6 Hz, 1H).
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I °
NO z
Step 2. 5-tert-ButyI-2-(2-/crt-butoxycarbonyloxy)ethoxy)-l-nitrobenzene: A
solution of 5-ferf-butyl-2-(2-hydroxyethoxy)-l -nitrobenzene (0.401 g, 1.68 mmol), di-
tert-butyl dicarbonate (0.46 mL, 2.0 mmol) and dimethylaminopyridine (0.006 g, 0.05
mmol) in CH 2 C1 2 (15 mL) was stirred at room temp, for 30 min, at which time TLC
indicated consumption of starting material. The resulting mixture was washed with
water (20 mL), dried (MgS0 4 ) and concentrated under reduced pressure. The residue
was purified by column chromatography (3% MeOH/97% CH 2 C1 2 ) to give the desired
product as a yellow oil (0.291 g, 51%): 'H-NMR (DMSO-d 6 ) 5 1.25 (s, 9H), 1.38 (s,
9H), 4.31 (br s, 4H), 7.27 (d, 7=9.2 Hz, 1H) 7.64 (dd, J=2.6, 8.8 Hz, 1H) 7.77 (d,
.7=2.6 Hz, 1H).
NH 2
Step3.5-rer/-Butyl-2-(2-tert-butoxycarbonyloxy)ethoxy)aniUne: To a mixture of
5-ter/-butyl-2-(2-fer/-butoxycarbonyloxy)ethoxy)-l -nitrobenzene (0.290 g, 0.86
mmol) and 5% Pd/C (0.058 g) in MeOH (2 mL) was ammonium formate (0.216 g,
3.42 mmol), and the resulting mixture was stirred at room temp, for 12 h, then was
filtered through a pad of Celite® with the aid of EtOH. The filtrate was concentrated
under reduced pressure and the residue was purified by column chromatography (2%
MeOH/98% CH 2 C1 2 ) tp give the desired product as a pale yellow oil (0.232 g, 87%):
TLC (20% EtO Ac/80% hexane) 0.63; 'H-NMR (DMSO-d 6 ) 8 1.17 (s, 9H), 1.39 (s,
9H), 4.03-4.06 (m, 2H), 4.30-4.31 (m, 2H), 4.54 (br s, 2H), 6.47 (dd, .7=2.2, 8.1 Hz,
1H) 6.64-6.67 (m, 2H).
All. General Method for Substituted Aniline Formation via Hydrogenation of
a Nitroarene
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4-(4-PyridinylmethyI)aniline: To a solution of 4-(4-nitrobenzyl)pyridine (7.0 g,
32.68 mmol) in EtOH (200 mL) was added 10% Pd/C (0.7 g) and the resulting slurry
was shaken under a H 2 atmosphere (50 psi) using a Parr shaker. After 1 h, TLC and
5 *H-NMR of an aliquot indicated complete reaction. The mixture was filtered through a
short pad of Celite®. The filtrate was concentrated in vacuo to afford a white solid (5.4
g, 90%): 'H-NMR (DMSO-d 6 ) 8 3.74 (s, 2H), 4.91 (br s, 2H), 6.48 (d, J=8.46 Hz,
2H), 6.86 (d, J-8.09 Hz, 2H), 7.16 (d, .7=5.88 Hz, 2H), 8.40 (d, J-5.88 Hz, 2H); EI-
MS m/z 184 (M + ). This material was used in urea formation reactions without further
10 purification.
A12. General Method for Substituted Aniline Formation via Dissolving Metal
Reduction of a Nitroarene
15 4-(2-Pyridinylthio)aniline: To a solution of 4-(2-pyridinylthio)-l -nitrobenzene
(Menai ST 3355A; 0.220 g, 0.95 mmol) and H2O (0.5 mL) in AcOH ( 5 mL) was
added iron powder (0.317 g, 5.68 mmol) and the resulting slurry stirred for 16 h at
room temp. The reaction mixture was diluted with EtOAc (75 mL) and H2O (50 mL),
basified to pH 10 by adding solid K 2 C0 3 in portions {Caution: foaming). The organic
20 layer was washed with a saturated NaCl solution, dried (MgS0 4 ), concentrated in
vacuo. The residual solid was purified by MPLC (30% EtOAc/70% hexane) to give
the desired product as a thick oil (0.135 g, 70%): TLC (30% EtOAc/70% hexanes)
0.20.
2A13a. General Method for Substituted Aniline Formation via Nitroarene Formation
Through Nucleophilic Aromatic Substitution, Followed by Reduction
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Step 1. l-Methoxy-4-(4-nitrophenoxy)benzene: To a suspension of NaH (95%,
1.50 g, 59 mmol) in DMF (100 mL) at room temp, was added dropwise a solution of
4-methoxyphenol (7.39 g, 59 mmol) in DMF (50 mL). The reaction was stirred 1 h,
then a solution of l-fluoro-4-nitrobenzene (7.0 g, 49 mmol) in DMF (50 mL) was
5 added dropwise to form a dark green solution. The reaction was heated at 95 °C
overnight, then cooled to room temp., quenched with H 2 0, and concentrated in vacuo.
The residue was partitioned between EtOAc (200 mL) and H 2 0 (200 mL) . The
organic layer was sequentially washed with H 2 0 (2 x 200 mL), a saturated NaHC0 3
solution (200 mL), and a saturated NaCl solution (200 mL), dried (Na^OJ, and
10 concentrated in vacuo. The residue was triturated (EtjO/hexane) to afford 1-
methoxy-4-(4-nitrophenoxy)benzene (12.2 g, 100%): 'H-NMR (CDC1 3 ) 5 3.83 (s,
3H), 6.93-7.04 (m, 6H), 8.18 (d, .7=9.2 Hz, 2H); EI-MS m/z 245 (M + ).
15 Step 2. 4-(4-Methoxyphenoxy)aniline: To a solution of 1 -methoxy-4-(4-
nitrophenoxy)benzene (12.0 g, 49 mmol) in EtOAc (250 mL) was added 5% Pt/C
(1.5 g) and the resulting slurry was shaken under a H 2 atmosphere (50 psi) for 18 h.
The reaction mixture was filtered through a pad of Celite® with the aid of EtOAc and
concentrated in vacuo to give an oil which slowly solidified (10.6 g, 100%): 'H-NMR
20 (CDC1 3 ) 8 3.54 (br s, 2H), 3.78 (s, 3H), 6.65 (d, J-8.8 Hz, 2H), 6.79-6.92 (m, 6H); EI-
MS m/z 215 (M + ).
A13b. General Method for Substituted Aniline Formation via Nitroarene Formation
Through Nucleophilic Aromatic Substitution, Followed by Reduction
25
Step 1. 3-(Trifluoromethyl)-4-(4-pyridinylthio)nitrobenzene: A solution of 4-
mercaptopyridine (2.8 g, 24 mmoles), 2-fluoro-5-nitrobenzotrifluoride (5 g, 23.5
mmoles), and potassium carbonate (6.1 g, 44.3 mmoles) in anhydrous DMF (80 mL)
was stirred at room temperature and under argon overnight. TLC showed complete
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reaction. The mixture was diluted with Et z O (100 mL) and water (100 mL) and the
aqueous layer was back-extracted with E^O (2 x 100 mL). The organic layers were
washed with a saturated NaCl solution (100 mL), dried (MgS0 4 ), and concentrated
under reduced pressure. The solid residue was triturated with EtjO to afford the
desired product as a tan solid (3.8 g, 54%): TLC (30% EtOAc/70% hexane) 1^0.06;
'H-NMR (DMSO-d 6 ) 8 7.33 (dd, .7=1.2, 4.2 Hz, 2H), 7.78 (d, .7=8.7 Hz, 1H), 8.46 (dd,
.7=2.4, 8.7Hz, 1H), 8.54-8.56 (m, 3H).
CF 3
H 2 N
Step 2. 3-(Trifluoromethyl)-4-(4-pyridinylthio)aniline: A slurry of 3-
10 trifluoromethyl-4-(4-pyridinylthio)nitrobenzene (3.8 g, 12.7 mmol), iron powder (4.0
g, 71.6 mmol), acetic acid (100 mL), and water (1 mL) were stirred at room temp, for
4 h. The mixture was diluted with Et 2 0 (100 mL) and water (100 mL). The aqueous
phase was adjusted to pH 4 with a 4 N NaOH solution. The combined organic layers
were washed with a saturated NaCl solution (100 mL), dried (MgS0 4 ), and
1 5 concentrated under reduced pressure. The residue was filtered through a pad of silica
(gradient from 50% EtOAc/50% hexane to 60% EtOAc/40% hexane) to afford the
desired product (3.3 g): TLC (50% EtOAc/50% hexane) R, 0.10; 'H-NMR (DMSO-d 6 )
6 6.21 (s, 2H), 6.84-6.87 (m, 3H), 7.10 (d, .7=2.4 Hz, 1H), 7.39 (d, 7=8.4 Hz, 1H), 8.29
(d, .7=6.3 Hz, 2H).
20
A13c. General Method for Substituted Aniline Formation via Nitroarene Formation
Through Nucleophilic Aromatic Substitution, Followed by Reduction
0 2 N \^
6
Step 1. 4-(2-(4-Phenyl)thiazolyl)thio-l-nitrobenzene: A solution of 2-mercapto-4-
25 phenylthiazole (4.0 g, 20.7 mmoles) in DMF (40 mL) was treated with l-fluoro-4-
nitrobenzene (2.3 mL, 21.7 mmoles) followed by K 2 C0 3 (3.18 g, 23 mmol), and the
mixture was heated at approximately 65 °C overnight. The reaction mixture was then
diluted with EtOAc (100 mL), sequentially washed with water (100 mL) and a
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5
saturated NaCl solution (100 mL), dried (MgS0 4 ) and concentrated under reduced
pressure. The solid residue was triturated with a EtjO/hexane solution to afford the
desired product (6.1 g): TLC (25% EtOAc/75% hexane) R^O.49; 'H-NMR (CDC1 3 ) S
7.35-7.47 (m, 3H), 7.58-7.63 (m, 3H), 7.90 (d, 7=6.9 Hz, 2H), 8.19 (d, J=9.0 Hz, 2H).
H 2 N
Step 2, 4-(2-(4-Phenyl)thiazolyI)thioaniline: 4-(2-(4-Phenyl)thiazolyl)thio-l -nitro-
benzene was reduced in a manner analagous to that used in the preparation of 3-
(trifluoromethyl)-4-(4-pyridinylthio)aniline: TLC (25% EtOAc/75% hexane) 0.18;
'H-NMR (CDC1 3 ) 6 3.89 (br s, 2H), 6.72-6.77 (m, 2H), 7.26-7.53 (m, 6H), 7.85-7.89
10 (m, 2H).
A13d. General Method for Substituted Aniline Formation via Nitroarene Formation
Through Nucleophilic Aromatic Substitution, Followed by Reduction
15 Step 1. 4-(6-Methyl-3-pyridinyloxy)-l-nitrobenzene: To a solution of 5-hydroxy-
2-methylpyridine (5.0 g, 45.8 mmol) and 1 -fluoro-4-nitrobenzene (6.5 g, 45.8 mmol)
in anh DMF (50 mL) was added K 2 C0 3 (13.0 g, 91.6 mmol) in one portion. The
mixture was heated at the reflux temp, with stirring for 18 h and then allowed to cool
to room temp. The resulting mixture was poured into water (200 mL) and extracted
20 with EtOAc (3 x 150 mL). The combined organics were sequentially washed with
water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (Na^OJ, and
concentrated in vacuo to afford the desired product (8.7 g, 83%). The this material
was carried to the next step without further purification.
25 Step 2. 4-(6-Methyl-3-pyridinyloxy)aniline: A solution of 4-(6-methyl-3-
pyridinyloxy)-! -nitrobenzene (4.0 g, 17.3 mmol) in EtOAc (150 mL) was added to
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10% Pd/C (0.500 g, 0.47 mmol) and the resulting mixture was placed under a H 2
atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was
then filtered through a pad of Celite® and concentrated in vacuo to afford the desired
product as a tan solid (3.2 g, 92%): EI-MS m/z 200 (M+).
, General Method for Substituted Aniline Formation via Nitroarene Formation
Through Nucleophilic Aromatic Substitution, Followed by Reduction
Step 1. 4-(3,4-Dimethoxyphenoxy)-l-nitrobenzene: To a solution of 3,4-
dimethoxyphenol (1.0 g, 6.4 mmol) and l-fluoro-4-nitrobenzene (700 ^L, 6.4 mmol)
in anh DMF (20 mL) was added K 2 C0 3 (1.8 g, 12.9 mmol) in one portion. The
mixture was heated at the reflux temp with stirring for 1 8 h and then allowed to cool
to room temp. The mixture was then poured into water (100 mL) and extracted with
EtOAc (3 x 100 mL). The combined organics were sequentially washed with water (3
x 50 mL) and a saturated NaCl solution (2 x 50 mL), dried (NaaSOJ, and concentrated
in vacuo to afford the desired product (0.8 g, 54%). The crude product was carried to
the next step without further purification.
Step 2. 4-(3,4-Dimethoxyphenoxy)aniIine: A solution of 4-(3,4-dimethoxy-
phenoxy)-l -nitrobenzene (0.8 g, 3.2 mmol) in EtOAc (50 mL) was added to 10%
Pd/C (0.100 g) and the resulting mixture was placed under a H 2 atmosphere (balloon)
and was allowed to stir for 1 8 h at room temp. The mixture was then filtered through
a pad of Celite® and concentrated in vacuo to afford the desired product as a white
solid (0.6 g, 75%): EI-MS m/z 245 (M+).
• General Method for Substituted Aniline Formation via Nitroarene Formation
Through Nucleophilic Aromatic Substitution, Followed by Reduction
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Step 1. 3-(3-Pyridinyloxy)-l-nitrobenzene: To a solution of 3-hydroxypyridine
(2.8 g, 29.0 mmol), l-bromo-3-nitrobenzene (5.9 g, 29.0 mmol) and copper®
bromide (5.0 g, 34.8 mmol) in anh DMF (50 mL) was added K 2 C0 3 (8.0 g, 58.1
mmol) in one portion. The resulting mixture was heated at the reflux temp, with
5 stirring for 1 8 h and then allowed to cool to room temp. The mixture was then poured
into water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organics
were sequentially washed with water (3 x 1 00 mL) and a saturated NaCl solution (2 x
100 mL), dried (NajSOJ, and concentrated in vacuo. The resulting oil was purified
by flash chromatography (30% EtO Ac/70% hexane) to afford the desired product (2.0
10 g, 32 %). This material was used in the next step without further purification.
Step 2. 3-(3-PyridinyIoxy)aniIine: A solution of 3-(3-pyridinyloxy)-l-
nitrobenzene (2.0 g, 9.2 mmol) in EtOAc (100 mL) was added to 10% Pd/C (0.200 g)
and the resulting mixture was placed under a H 2 atmosphere (balloon) and was
15 allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of
Celite® and concentrated in vacuo to afford the desired product as a red oil (1.6 g,
94%): EI-MS m/z 186 (M + ).
A13g. General Method for Substituted Aniline Formation via Nitroarene Formation
20 Through Nucleophilic Aromatic Substitution, Followed by Reduction
Stepl. 3-(5-Methyl-3-pyridinyloxy)-l-nitrobenzene: To a solution of 3-hydroxy-
5-methylpyridine (5.0 g, 45.8 mmol), l-bromo-3 -nitrobenzene (12.0 g, 59.6 mmol)
and copper® iodide (10.0 g, 73.3 mmol) in anh DMF (50 mL) was added K 2 C0 3
25 (13.0 g, 91.6 mmol) in one portion. The mixture was heated at the reflux temp, with
stirring for 18 h and then allowed to cool to room temp. The mixture was then poured
into water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organics
were sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x
100 mL), dried (Na^OJ, and concentrated in vacuo . The resulting oil was purified
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by flash chromatography (30% EtO Ac/70% hexane) to afford the desired product (1.2
Step 2. 3-(5-Methyl-3-pyridinyloxy)-l-nitrobenzene: A solution of 3-(5-methyl-3-
5 pyridinyloxy)-l -nitrobenzene (1.2 g, 5.2 mmol) in EtOAc (50 mL) was added to 10%
Pd/C (0.100 g) and the resulting mixture was placed under a H 2 atmosphere (balloon)
and was allowed to stir for 18 h at room temp. The mixture was then filtered through
A13h. General Method for Substituted Aniline Formation via Nitroarene Formation
Through Nucleophilic Aromatic Substitution, Followed by Reduction
Step 1. 5-Nitro-2-(4-methylphenoxy)pyridine: To a solution of 2-chloro-5-
15 nitropyridine (6.34 g, 40 mmol) in DMF (200 mL) were added of 4-methylphenol (5.4
g, 50 mmol, 1.25 equiv) and K 2 C0 3 (8.28 g, 60 mmol, 1.5 equiv). The mixture was
stirred overnight at room temp. The resulting mixture was treated with water (600
mL) to generate a precipitate. This mixture was stirred for 1 h, and the solids were
separated and sequentially washed with a 1 N NaOH solution (25 mL), water (25 mL)
20 and pet ether (25 mL) to give the desired product (7.05 g, 76%): mp 80-82 °C; TLC
(30% EtOAc/70% pet ether) R, 0.79; 'H-NMR (DMSO-d 6 ) 5 2.31 (s, 3H), 7.08 (d,
J=8.46 Hz, 2H), 7.19 (d, J=9.20 Hz, 1H), 7.24 (d, J=8.09 Hz, 2H), 8.58 (dd, J=2.94,
8.82 Hz, 1H), 8.99 (d, J=2.95 Hz, 1H); FAB-MS m/z (rel abundance) 231 ((M+H) + ),
100%).
g, 13%).
a pad of Celite® and concentrated in vacuo to afford the desired product as a red oil
(0.9 g, 86%): CI-MS m/z 201 ((M+H) + ).
25
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Step 2. 5-Amino-2-(4-methyIphenoxy)pyridine Dihydrochloride: A solution 5-
nitro-2-(4-methylphenoxy)pyridine (6.94 g, 30 mmol, 1 eq) and EtOH (10 mL) in
EtOAc (190 mL) was purged with argon then treated with 10% Pd/C (0.60 g). The
reaction mixture was then placed under a H 2 atmosphere and was vigorously stirred
for 2.5 h. The reaction mixture was filtered through a pad of Celite®. A solution of
HC1 in Et 2 0 was added to the filtrate was added dropwise. The resulting precipitate
was separated and washed with EtOAc to give the desired product (7.56 g, 92%): mp
208-210 °C (dec); TLC (50% EtOAc/50% pet ether) 0.42; *H-NMR (DMSO-d 6 ) 6
2.25 (s, 3H), 6.98 (d, J-8.45 Hz, 2H), 7.04 (d, J=8.82 Hz, 1H), 7.19 (d, J=8.09 Hz,
2H), 8.46 (dd, J=2.57, 8.46 Hz, 1H), 8.63 (d, 7=2.57 Hz, 1H); EI-MS m/z (rel
abundance) (M\ 100%).
General Method for Substituted Aniline Formation via Nitroarene Formation
Through Nucleophilic Aromatic Substitution, Followed by Reduction
Step 1. 4-(3-Thienylthio)-l-nitrobenzene: To a solution of 4-nitrothiophenol
(80%pure; 1.2 g, 6.1 mmol), 3-bromothiophene (1.0 g, 6.1 mmol) and copper(II)
oxide (0.5 g, 3.7 mmol) in anhydrous DMF (20 mL) was added KOH (0.3 g, 6.1
mmol), and the resulting mixture was heated at 130 °C with stirring for 42 h and then
allowed to cool to room temp. The reaction mixture was then poured into a mixture
of ice and a 6N HC1 solution (200 mL) and the resulting aqueous mixture was
extracted with EtOAc (3 x 100 mL). The combined organic layers were sequentially
washed with a 1M NaOH solution (2 x 100 mL) and a saturated NaCl solution (2 x
100 mL), dried (MgSO A ), and concentrated in vacuo . The residual oil was purified by
MPLC (silica gel; gradient from 10% EtO Ac/90% hexane to 5% EtO Ac/95% hexane)
to afford of the desired product (0.5 g, 34%). GC-MS m/z 237 (M + ).
H 2 N ^
Step 2. 4-(3-Thienylthio)aniline: 4-(3-Thienylthio)-l -nitrobenzene was reduced to
the aniline in a manner analogous to that described in Method Bl .
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A13j. General Method for Substituted Aniline Formation via Nitroarene
Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction
H 2 N
5 4-(5-Pyrimininyloxy)aniline: 4-Aminophenol (1.0 g, 9.2 mmol) was dissolved in
DMF (20 mL) then 5-bromopyrimidine (1.46 g, 9.2 mmol) and K2CO3 (1.9 g, 13.7
mmol) were added. The mixture was heated to 100 °C for 18 h and at 130 °C for 48 h
at which GC-MS analysis indicated some remaining starting material. The reaction
mixture was cooled to room temp, and diluted with water (50 mL). The resulting
10 solution was extracted with EtOAc (100 mL). The organic layer was washed with a
saturated NaCl solution (2 x 50 mL), dried (MgS0 4 ), and concentrated in vacuo. The
residular solids were purified by MPLC (50% EtOAc/50% hexanes) to give the
desired amine (0.650 g, 38%).
lA13k- General Method for Substituted Aniline Formation via Nitroarene Formation
Through Nucleophilic Aromatic Substitution, Followed by Reduction
25
OMe
Step 1. 5-Bromo-2-methoxypyridine: A mixture of 2,5-dibromopyridine (5.5 g,
23.2 mmol) and NaOMe (3.76g, 69.6 mmol) in MeOH (60 mL) was heated at 70 °C
20 in a sealed reaction vessel for 42 h, then allowed to cool to room temp. The reaction
mixture was treated with water (50 mL) and extracted with EtOAc (2 x 100 mL). The
combined organic layers were dried (Na^Q,) and concentrated under reduced
pressure to give a pale yellow, volatile oil (4.1g, 95% yield): TLC (10% EtOAc / 90%
hexane) 0.57.
HO — k v^OMe
Step 2. 5-Hydroxy-2-methoxypyridine: To a stirred solution of 5-bromo-2-
methoxypyridine (8.9 g, 47.9 mmol) in THF (175 mL) at -78 °C was added an n-
butyllithium solution (2.5 M in hexane; 28.7 mL, 71.8 mmol) dropwise and the
resulting mixture was allowed to stir at -78 °C for 45 min. Trimethyl borate (7.06
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10
mL, 62.2 mmol) was added via syringe and the resulting mixture was stirred for an
additional 2 h. The bright orange reaction mixture was warmed to 0 °C and was
treated with a mixture of a 3 N NaOH solution (25 mL, 71.77 mmol) and a hydrogen
peroxide solution (30%; approx. 50 mL). The resulting yellow and slightly turbid
reaction mixture was warmed to room temp, for 30 min and then heated to the reflux
temp, for 1 h. The reaction mixture was then allowed to cool to room temp. The
aqueous layer was neutralized with a IN HC1 solution then extracted with E^O (2 x
100 mL). The combined organic layers were dried (Na^OJ and concentrated under
reduced pressure to give a viscous yellow oil (3.5g, 60%).
0 2 N N OMe
Step 3. 4-(5-(2-Methoxy)pyridyl)oxy-l-nitrobenzene: To a stirred slurry of NaH
(97%, 1.0 g, 42 mmol) in anh DMF (100 mL) was added a solution of 5-hydroxy-2-
methoxypyridine (3.5g, 28 mmol) in DMF (100 mL). The resulting mixture was
allowed to stir at room temp, for 1 h, 4-fluoronitrobenzene (3 mL, 28 mmol) was
1 5 added via syringe. The reaction mnixture was heated to 95 °C overnight, then treated
with water (25 mL) and extracted with EtOAc (2 x 75 mL). The organic layer was
dried (MgS0 4 ) and concentrated under reduced pressure. The residual brown oil was
crystalized EtOAc/hexane) to afford yellow crystals (5.23 g, 75%).
HoN" OMe
20 Step 4, 4-(5-(2-Methoxy)pyridyl)oxyaniline: 4-(5-(2-Methoxy)pyridyl)oxy-l-
nitrobenzene was reduced to the aniline in a manner analogous to that described in
Method B3d, Step2.
A14a. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic
25 Substitution using a Halopyridine
3_(4-Pyridinylthio)aniline: To a solution of 3-aminothiophenol (3.8 mL, 34 mmoles)
in anh DMF (90mL) was added 4-chloropyridine hydrochloride (5.4 g, 35.6 mmoles)
followed by K 2 C0 3 (16.7 g, 121 mmoles). The reaction mixture was stirred at room
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temp, for 1.5 h, then diluted with EtOAc (100 mL) and water (lOOmL). The aqueous
layer was back-extracted with EtOAc (2 x 100 mL). The combined organic layers
were washed with a saturated NaCl solution (100 mL), dried (MgS0 4 ), and
concentrated under reduced pressure. The residue was filtered through a pad of silica
(gradient from 50% EtOAc/50% hexane to 70% EtOAc/30% hexane) and the resulting
material was triturated with a Et z O/hexane solution to afford the desired product (4.6
g, 66%): TLC (100 % ethyl acetate) R^- 0.29; 'H-NMR (DMSO-d 6 ) 8 5.41 (s, 2H),
6.64-6.74 (m, 3H), 7.01 (d, J=4.8, 2H), 7.14 (t, J=7.8 Hz, 1H), 8.32 (d, J=4.8, 2H).
. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic
Substitution using a Halopyridine
4-(2-Methyl-4-pyridinyIoxy)aniline: To a solution of 4-aminophenol (3.6 g, 32.8
mmol) and 4-chloropicoline (5.0 g, 39.3 mmol) in anh DMPU (50 mL) was added
potassium tert-butoxide (7.4 g, 65.6 mmol) in one portion. The reaction mixture was
heated at 100 °C with stirring for 18 h, then was allowed to cool to room temp. The
resulting mixture was poured into water (200 mL) and extracted with EtOAc (3 x 150
mL). The combined extracts were sequentially washed with water (3 x 100 mL) and a
saturated NaCl solution (2 x 100 mL), dried (NajSO^, and concentrated in vacuo.
The resulting oil was purified by flash chromatography (50 % EtO Ac/50% hexane) to
afford the desired product as a yellow oil (0.7 g, 9%): CI-MS m/z 201 ((M+H) + ).
A14c. General Method for Substituted Aniline Synthesis via Nucleophilic
Aromatic Substitution using a Halopyridine
Step 1. Methyl(4-nitrophenyl)-4-pyridylamine: To a suspension of iV-methyl-4-
nitroaniline (2.0 g, 13.2 mmol) and K 2 C0 3 (7.2 g, 52.2 mmol) in DMPU (30mL) was
added 4-chloropyridine hydrochloride (2.36 g, 15.77 mmol). The reaction mixture
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was heated at 90 °C for 20 h, then cooled to room temperature. The resulting mixture
was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic
layer was washed with water (100 mL), dried (Na^OJ and concentrated under
reduced pressure. The residue was purified by column chromatography (silica gel,
5 gradient from 80% EtOAc /20% hexanes to 100% EtOAc) to afford methyl(4-
nitrophenyl)-4-pyridylamine (0.42 g)
Step 2. Methyl(4-aminophenyl)-4-pyridylamine: Methyl(4-nitrophenyl)-4-
A15. General Method of Substituted Aniline Synthesis via Phenol Alkylation
Followed by Reduction of a Nitroarene
Step 1. 4-(4-Butoxyphenyl)thio-l-nitrobenzene: To a solution of 4-(4-nitrophenyl-
15 thio)phenol (1.50 g, 6.07 mmol) in anh DMF (75 ml) at 0 °C was added NaH (60% in
mineral oil, 0.267 g, 6.67 mmol). The brown suspension was stirred at 0 °C until gas
evolution stopped (15 min), then a solution of iodobutane (1.12 g, .690 ml, 6.07
mmol) in anh DMF (20 mL) was added dropwise over 15 min at 0 °C. The reaction
was stirred at room temp, for 18 h at which time TLC indicated the presence of
20 unreacted phenol, and additional iodobutane (56 mg, 0.035 mL, 0.303 mmol, 0.05
equiv) and NaH (13 mg, 0.334 mmol) were added. The reaction was stirred an
additional 6 h room temp., then was quenched by the addition of water (400 mL). The
resulting mixture was extracted with Et 2 0 (2 x 500 mL). The combibed organics were
washed with water (2 x 400 mL), dried (MgSOJ, and concentrated under reduced
25 pressure to give a clear yellow oil, which was purified by silica gel chromatography
(gradient from 20% EtOAc/80% hexane to 50% EtOAc/50% hexane) to give the
product as a yellow solid (1.24 g, 67%): TLC (20% EtOAc/80% hexane) R^O.75; , H-
NMR (DMSO-d 6 ) 8 0.92 (t, J= 7.5 Hz, 3H), 1.42 (app hex, J=7.5 Hz, 2H), 1.70 (m,
pyridylamine was reduced in a manner analogous to that described in Method Bl.
10
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2H), 4.01 (t, ./= 6.6 Hz, 2H), 7.08 (d, J=8J Hz, 2H), 7.17 (d, J=9 Hz, 2H), 7.51 (d,
J= 8.7 Hz, 2H), 8.09 (d, J= 9 Hz, 2H).
S
Step 2. 4-(4-ButoxyphenyI)thioaniIine: 4-(4-Butoxyphenyl)thio-l -nitrobenzene was
5 reduced to the aniline in a manner analagous to that used in the preparation of 3-
(trifiuoromethyl)-4-(4-pyridinylthio)aniline (Method B3b, Step 2): TLC (33%
EtOAc/77% hexane) R^.0.38.
A16. General Method for Synthesis of Substituted Anilines by the Acylation of
10 Diaminoarenes
l-UN
4-(4-ter^Butoxycarbamoylbenzyl)aniline: To a solution of 4,4'-methylenedianiline
(3.00 g, 15.1 mmol) in anh THF (50 mL) at room temp was added a solution of di-
tert-butyl dicarbonate (3.30 g, 15.1 mmol) in anh THF (10 mL). The reaction
15 mixture was heated at the reflux temp, for 3 h, at which time TLC indicated the
presence of unreacted methylenedianiline. Additional di-terf-butyl dicarbonate (0.664
g, 3.03 mmol, 0.02 equiv) was added and the reaction stirred at the reflux temp, for 16
h. The resulting mixture was diluted with Et^O (200 mL), sequentially washed with a
saturated NaHC0 3 solution (100 ml), water (100 mL) and a saturated NaCl solution
20 (50 mL), dried (MgS04), and concentrated under reduced pressure. The resulting
white solid was purified by silica gel chromatography (gradient from 33%
EtOAc/67% hexane to 50% EtOAc/50% hexane) to afford the desired product as a
white solid ( 2.09 g, 46%): TLC (50% EtOAc/50% hexane) IL- 0.45; 'H-NMR
(DMSO-d 6 ) 8 1.43 (s, 9H), 3.63 (s, 2H), 4.85 (br s, 2H), 6.44 (d, J=8.4 Hz, 2H),
25 6.80 (d, J=8.1 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 7.28 (d, J=S. 1 Hz, 2H), 9.18 (br s,
1H); FAB-MS m/z 298 (M + ).
A17. General Method for the Synthesis of Aryl Amines via Electrophilic Nitration
Followed by Reduction
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0 2 N
10
Step 1. 3-(4-Nitrobenzyl)pyridine: A solution of 3-benzylpyridine (4.0 g,
23.6 mmol) and 70% nitric acid (30 mL) was heated overnight at 50 °C. The resulting
mixture was allowed to cool to room temp, then poured into ice water (350 mL). The
aqueous mixture then made basic with a IN NaOH solution, then extracted with E^O
(4 x 100 mL). The combined extracts were sequentially washed with water (3 x 100
mL) and a saturated NaCl solution (2 x 100 mL), dried (N^SOJ, and concentrated in
vacuo. The residual oil was purified by MPLC (silica gel; 50 % EtOAc/50% hexane)
then recrystallization (EtOAc/hexane) to afford the desired product (1.0 g, 22%): GC-
MS m/z 214 (M + ).
H-jN
Step 2. 3-(4-Pyridinyl)methylaniline: 3-(4-Nitrobenzyl)pyridine was reduced to the
aniline in a manner analogous to that described in Method B 1 .
1A18. General Method for Synthesis of Aryl Amines via Substitution with Nitrobenzyl
Halides Followed by Reduction
Step 1. 4-(l-ImidazoIylmethyl)-l-nitrobenzene: To a solution of imidazole (0.5 g,
7.3 mmol) and 4-nitrobenzyl bromide (1 .6 g, 7.3 mmol) in anh acetonitrile (30 mL)
20 was added K 2 C0 3 (1.0 g, 7.3 mmol). The resulting mixture was stirred at rooom
temp, for 1 8 h and then poured into water (200 mL) and the resulting aqueous solution
wasextracted with EtOAc (3 x 50 mL). The combined organic layers were
sequentially washed with water (3 x 50 mL) and a saturated NaCl solution (2 x 50
mL), dried (MgS0 4 ), and concentrated in vacuo. The residual oil was purified by
25 MPLC (silica gel; 25% EtO Ac/75% hexane) to afford the desired product (1.0 g,
91%): EI-MS m/z 203 (M + ).
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Step 2. 4-(l-ImidazoIylmethyl)aniline: 4-(l -Imidazolylmethyl)- 1 -nitrobenzene was
reduced to the aniline in a manner analogous to that described in Method B2.
A19. Formation of Substituted Hydroxymethylanilines by Oxidation of Nitrobenzyl
10
15
20
Compounds Followed by Reduction
OH
0 2 N
Step 1. 4-(l-Hydroxy-l-(4-pyridyl)methyl-l-nitrobenzene: To a stirred solution
of 3-(4-nitrobenzyl)pyridine (6.0 g, 28 mmol) in CH 2 C1 2 (90 mL) was added m-CPBA
(5.80 g, 33.6 mmol) at 10 °C, and the mixture was stirred at room temp, overnight.
The reaction mixture was successively washed with a 10% NaHS0 3 solution (50 mL),
a saturated K 2 C0 3 solution (50 mL) and a saturated NaCl solution (50 mL), dried
(MgS0 4 ) and concentrated under reduced pressure. The resulting yellow solid (2.68
g) was dissolved in anh acetic anhydride (30 mL) and heated at the reflux temperature
overnight. The mixture was concentrated under reduced pressure. The residue was
dissolved in MeOH (25 mL) and treated with a 20% aqueous NH 3 solution (30 mL).
The mixture was stirred at room temp, for 1 h, then was concentrated under reduced
pressure. The residue was poured into a mixture of water (50 mL) and CH 2 C1 2 (50
mL). The organic layer was dried (MgS0 4 ), concentrated under reduced pressure, and
purified by column chromatography (80% EtOAc/ 20% hexane) to afford the desired
product as a white solid. (0.53 g, 8%): mp 110-118 °C; TLC (80% EtOAc/20%
hexane) 0.12; FAB-MS m/z 367 ((M+H) + , 100%).
25
OH
H 2 N
Step 2. 4-(l-Hydroxy-l-(4-pyridyl)methylaniline: 4-(l -Hydroxy- l-(4-pyridyl)-
methyl-1 -nitrobenzene was reduced to the aniline in a manner analogous to that
described in Method B3d, Step2.
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A20. Formation of 2-(W-methylcarbamoyl)pyridines via the Menisci reaction
O
Step 1. 2-(iV-methylcarbamoyl)-4-chloropyridine. (Caution: this is a highly
hazardous, potentially explosive reaction.) To a solution of 4-chloropyridine (10.0 g)
in N-methylformamide (250 mL) under argon at ambient temp was added cone. H 2 S0 4
(3.55 mL) (exotherm). To this was added H 2 0 2 (17 mL, 30% wt in H20) followed
by FeS0 4 7H20 (0.55 g) to produce an exotherm. The reaction was stirred in the dark
at ambient temp for lh then was heated slowly over 4 h at 45 °C. When bubbling
subsided,the reaction was heated at 60 °C for 16 h. The opaque brown solution was
diluted with H20 (700 mL) followed by a 10% NaOH solution (250 mL). The
aqueous mixture was extracted with EtOAc (3 x 500 mL) and the organic layers were
washed separately with a saturated NaCl solution (3 x 150 mlL. The combined
organics were dried (MgS0 4 ) and filtered through a pad of silica gel eluting with
EtOAc. The solvent was removed in vacuo and the brown residue was purified by
silica gel chromatography (gradient from 50% EtOAc / 50% hexane to 80% EtOAc /
20% hexane). The resulting yellow oil crystallized at 0 °C over 72 h to give 2-(N-
methylcarbamoyl)-4-chloropyridine in yield (0.61 g, 5.3%): TLC (50% EtOAc/50%
hexane) % 0.50; MS; 'H NMR (CDC1 3 ): d 8.44 (d, 1 H, J = 5.1 Hz, CBN), 8.21 (s,
1H, CHCCO), 7.96 (b s, 1H, NH), 7.43 (dd, 1H, J = 2.4, 5.4 Hz, C1CHCN), 3.04 (d,
3H, J = 5.1 Hz, methyl); CI-MS m/z 171 ((M+H)+).
A2 1 . Generalmethod for the Synthesis of (D-Sulfonylphenyl Anilines
0 2 N
Step 1. 4-(4-Methylsulfonylphenoxy)-l-nitrobenzene: To a solution of 4-(4-
methylthiophenoxy)-l-ntirobenzene (2 g, 7.66 mmol) in CH 2 C1 2 (75 mL) at 0 °C was
slowly added wiCPBA (57-86%, 4 g), and the reaction mixture was stirred at room
temperature for 5 h. The reaction mixture was treated with a 1 N NaOH solution (25
mL). The organic layer was sequentially washed with a IN NaOH solution (25 mL),
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water (25 mL) and a saturated NaCl solution (25 mL), dried (MgS0 4 ), and
concentrated under reduced pressure to give 4-(4-methylsulfonylphenoxy)-l-
nitrobenzene as a solid (2.1 g).
Step 2. 4-(4-MethylsuIfonylphenoxy)-l-aniIine: 4-(4-Methylsulfonylphenoxy)-l-
nitrobenzene was reduced to the aniline in a manner anaologous to that described in
Method B3d, step 2.
A22. General Method for Synthesis of co-Alkoxy-co-carboxyphenyl Anilines
O
Step 1. 4-(3-Methoxycarbonyl-4-methoxyphenoxy)-l-nitrobenzene: To a solution
of -(3-carboxy-4-hydroxyphenoxy)-l-nitrobenzene (prepared in a manner analogous
to that described in Method B3a, step 1, 12 mmol) in acetone (50 mL) was added
K 2 C0 3 (5 g) and dimethyl sulfate (3.5 mL). The resulting mixture was heated aaaaaat
the reflux tempoerature overnight, then cooled to room temperature and filtered
through a pad of Celite® The resulting solution was concentrrated under reduced
pressure, absorbed onto silica gel, and purified by column chromatography (50%
EtOAc / 50% hexane) to give 4-(3-methoxycarbonyl-4-methoxyphenoxy)-l-
nitrobenzene as a yellow powder (3 g): mp 115 118 °C.
O
Step 2. 4-(3-Carboxy-4-methoxyphenoxy)-l-nitrobenzene: A mixture of 4-(3-
methoxycarbonyl-4-methoxyphenoxy)-l -nitrobenzene (1.2 g), KOH (0.33 g),and
water (5 mL) in MeOH (45 mL) was stirred at room temperature overnight and then
heated at the reflux temperature for 4 h. The resulting mixture was cooled to room
temperature and concentrated under reduced pressure. The residue was dissolved in
water (50 mL), and the aqueous mixture was made acidic with a IN HC1 solution.
The resulting mixture was extracted with EtOAc (50 mL). The organic layer was
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dried (MgS0 4 ) and concentrated under reduced pressure to give 4-(3-carboxy-4-
methoxyphenoxy)-! -nitrobenzene (1.04 g).
B. General Methods of Urea Formation
Bla. General Method for the Reaction of an Aryl Amine with an Aryl
Isocyanate
A^-(5-^r/-Butyl-2-(3-tetrahydrofuranyloxy)phenyl)-iV , -(4-methylphenyl)urea: To
a solution of 5-^rr-butyl-2-(3-tetrahydrofuranyloxy)aniline (0.078 g, 0.33 mmol) in
toluene (2.0 mL) was added /?-tolyl isocyanate (0.048 g, 0.36 mmol) and the resulting
mixture was allowed to stir at room temp, for 8 h to produce a precipitate. The
reaction mixture was filtered and the residue was sequentially washed with toluene
and hexanes to give the desired urea as a white solid (0.091 g, 75%): mp 229-231 °C;
'H-NMR (DMSO-d 6 ) 6 1.30 (s, 9H), 1.99-2.03 (m, 1H), 2.19-2.23 (m, 4H), 3.69-3.76
(m, 1H), 3.86-3.93 (m, 3H), 4.98-5.01 (m, 1H), 6.81-6.90 (m, 2H), 7.06 (d, J=S.09 Hz,
2H, 7.32 (d, J=8.09 Hz, 2H), 7.84 (s, 1H), 8.22 (d, J=2.21 Hz, 1H), 9.26 (s, 1H).
Bib. General Method for the Reaction of an Aryl Amine with an Aryl
Isocyanate
^-(l-Methoxy-S-^rifluoromethanesulfonyOphenyO-TVX^methylphenyOurea: p-
Tolyl isocyanate (0.19 mL, 1.55 mmol) was added to a solution of 2-methoxy-5-
(trifluoromethanesulfonyl)aniline (0.330 g> 1.29 mmol) in EtOAc (5 mL), and the
CF 3
o=s=o
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reaction mixture was stirred at room temp, for 1 8 h. The resulting precipitate was
collected by filtration and washed with Et 2 0 to give a white solid (0.28 g). This
material was then purified by HPLC (C-18 column, 50% CH 3 CN/50% H 2 0) and the
resulting solids were triturated with Et 2 0 to provide the title compound (0.198 g): 1 H-
5 NMR (CDC1 3 ) 5 7.08 (d, 7=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 7.40 (d, J-8.8 Hz,
1H), 7.71 (dd, J=2.6, 8.8 Hz, 1H), 8.66 (s, 1H), 8.90 (d, JK2.6 Hz, 1H), 9.36 (s, 1H);
FAB-MS m/z 389 ((M+l) + )-
Blc. General Method for the Reaction of an Aryl Amine with an Aryl
10 Isocyanate
CHF 2
o=s=o
A r -(2-Methoxy-5-(difluoromethanesuIfonyl)phenyl)-A^ , -(4-methylphenyI)urea: p-
Tolyl isocyanate (0.058 mL, 0.46 mmol) was added to a solution of 2-methoxy-5-
(difluoromethanesulfonyl)aniline (0.100 g, 0.42 mmol) in EtOAc (0.5 mL) and the
15 resulting mixture was stirred at room temp, for 3 d. The resulting precipitate was
filtered and washed with Et 2 0 to provide the title compound as a white solid (0.092
g): 'H-NMR (CDCI3) 5 2.22 (s, 3H) 4.01 (s, 3H), 7.02-7.36 (m, 6H), 7.54 (dd, J=2.4,
8.6 Hz, 1H), 8.57 (s, 1H), 8.79 (d, J=2.6 Hz, 1H), 9.33 (s, 1H); EI-MS m/z 370 (M + ).
20 Bid, General Method for the Reaction of an Aryl Amine with an Aryl
Isocyanate
A^(2,4-Dimethoxy-5-(trifluoromethyl)phenyl)-A r, -(4-methylphenyl)urea: /?-Tolyl
isocyanate (0.16 mL, 1.24 mmol) was added to a solution of 2,4-dimethoxy-5-
25 (trifluoromethyl)aniline (0.25 g, 1.13 mmol) in EtOAc (3 mL) and the resulting
mixture was stirred at room temp, for 18 h. A resulting precipitate was washed with
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Et 2 0 to give the title compound as a white solid (0.36 g): 'H-NMR (CDC1 3 ) 5 2.21 (s,
3H). 3.97 (s, 3H), 3.86 (s, 3H), 6.88 (s, 1H), 7.05 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.5
Hz, 2H), 8.13 (s, 1H), 8.33 (s, 1H), 9.09 (s, 1H); FAB-MS m/z 355 ((M+l) + ).
Ble. General Method for the Reaction of an Aryl Amine with an Aryl
Isocyanate
^-(S-Methoxy-l-naphthylJ-A^'-Cl-naphthyOurea: To a solution of 2-amino-3-
methoxynaphthalene (0.253 g, 1.50 mmol) in CH 2 C1 2 (3 mL) at room temp, was added
a solution of 1-naphthyl isocyanate (0.247 g, 1.50 mmol) in CH 2 C1 2 (2 mL) and the
resulting mixture was allowed to stir overnight. The resulting precipitate was
separated and washed with CH 2 C1 2 to give the desired urea as a white powder (0.450
g, 90%): mp 235-236 °C; 'H-NMR (DMSO-d 6 ) 8 4.04 (s, 3H), 7.28-7.32 (m, 2H),
7.38 (s, 1H), 7.44-7.72 (m, 6H), 7.90-7.93 (m, 1H), 8.05-8.08 (m, 1H), 8.21-8.24 (m,
1H), 8.64 (s, 1H), 9.03 (s, 1H), 9.44 (s, 1H); FAB-MS m/z 343 ((M+H) + ).
Blf. General Method for the Reaction of an Aryl Amine with an Aryl
Isocyanate
7V-(5-^r/-Butyl-2-(2-rer^-butoxycarbonyloxy)ethoxy)phenyl)-A^-(4-
methylphenyl)urea: A mixture of 5-terr-butyl-2-(2-terf-
butoxycarbonyloxy)ethoxy)aniline (Method A10, 0.232 g, 0.75 mmol) and /?-tolyl
isocyanate (0.099 mL, 0.79 mmol) in EtOAc (1 mL) was stirred at room temp, for 3 d
to produce a solid, which was separated. The filtrate was purified by column
chromatography (100% CH 2 C1 2 ) and the residue was triturated (Et 2 0/hexane) to give
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the desired product (0.262 g, 79%): mp 155-156 °C; TLC (20% EtOAc/80% hexane)
R^O.49; 'H-NMR (DMSO-d 6 ) 6 1.22 (s, 9H), 1.37 (s, 9H), 2.21 (s, 3H), 4.22-4.23 (m,
2H), 4.33-4.35 (m, 2H), 6.89-7.00 (m, 4H), 7.06 (d, .7=8.5 Hz, 2H), 7.32 (d, .7=8.1 Hz,
2H), 7.96 (s, 1H); 8.22 (d, .7=1.5 Hz, 1H), 9.22 (s, 1H); FAB-MS m/z (rel abundance)
5 443 ((M+H) + , 6%).
B2a. General Method for Reaction of an Aryl Amine with Phosgene Followed by
Addition of a Second Aryl Amine
CF,
A^-(2-Methoxy-5-(trifluoromethyl)phenyl)-A r, -(3-(4-pyridinylthio)phenyl)urea:
To a solution of pyridine (0.61 mL, 7.5 mmol, 3.0 equiv) and phosgene (20% in
toluene; 2.65 mL, 5.0 mmol, 2.0 equiv) in CH 2 C1 2 (20 mL) was added 2-methoxy-5-
15 (trifluoromethyl)aniline (0.48 g, 2.5 mmol) at 0 °C. The resulting mixture was
allowed warm to room temp, stirred for 3 h, then treated with anh. toluene (100 mL)
and concentrated under reduced pressure. The residue was suspended in a mixture of
CH 2 C1 2 (10 mL) and anh. pyridine (10 mL) and treated with 3-(4-pyridinylthio)aniline
(0.61 g, 2.5 mmol, 1.0 equiv). The mixture was stirred overnight at room temp., then
20 poured into water (50 mL) and extracted with CH 2 C1 2 (3 x 25 mL). The combined
organic layers were dried (MgS0 4 ) and concentrated under reduced pressure. The
residue was dissolved in a minimal amount of CH 2 C1 2 and treated with pet. ether to
give the desired product as a white precipitate (0.74 g, 70%): mp 202 °C; TLC (5%
acetone/95% CH 2 C1 2 ) R^O.09; 'H-NMR (DMSO-de) 8 7.06 (d, .7=5.5 Hz, 2H), 7.18
25 (dd, .7=2.4, 4.6 Hz, 2H), 7.3 1 (dd, J= 2.2, 9.2 Hz, 1H), 7.44 (d, .7=5.7 Hz, 1H), 7.45 (s,
1H), 7.79 (d, .7=2.2 Hz, 1H), 8.37 (s, 2H), 8.50 (dd, 7=2.2, 9.2 Hz, 2H), 9.63 (s, 1H),
9.84 (s, 1H); FAB-MS m/z 420 ((M+H)+, 70%).
B2b. General Method for Reaction of an Aryl Amine with Phosgene Followed by
30 Addition of a Second Aryl Amine
10
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CF 3
A^-(2-Methoxy-5-(trifluoromethyI)phenyl)-A^ , -(4-(4-pyridinyIthio)phenyl)urea: To
a solution of pyridine (0.61 mL, 7.5 mmol, 3.0 equiv) and phosgene (20% in toluene;
2.65 mL, 5.0 mmol, 2.0 equiv) in CH 2 C1 2 (20 mL) was added 4-(4-
pyridinylthio)aniline (0.506 g, 2.5 mmol) at 0 °C. After stirring for 3 h at room temp.,
the mixture was treated with anh. toluene (100 mL) then concentrated under reduced
pressure. The residue was suspended in a mixture of CH 2 C1 2 (10 mL) and anh.
pyridine (10 mL) and treated with 2-methoxy-5-(trifluoromethyl)aniline (0.50 g, 2.5
mmol, 1.0 equiv). After stirring the mixture overnight at room temp., it was poured
into a 1 N NaOH solution (50 mL) and extracted with CH 2 C1 2 (3 x 25 mL). The
combined organic layers were dried (MgS0 4 ) and concentrated under reduced
pressure to give the desired urea (0.74 g, 71%): mp 215 °C; TLC (5% acetone/95%
CH 2 C1 2 ) IV 0.08; 'H-NMR (DMSO-d 6 ) 5 3.96 (s, 3H), 6.94 (dd, J=L1, 4.8 Hz, 2H),
7.19 (d, J=8.4 Hz, 1H), 7.32 (dd, JN2.2, 9.3 Hz, 1H), 7.50 (d, J-8.8 Hz, 2H), 7.62 (d,
J=8.8 Hz, 2H), 8.32 (d, J=5A Hz, 2H), 8.53 (d, J-0.7 Hz, 1H), 8.58 (s, 1H), 9.70 (s,
1H); FAB-MS m/z 420 ((M+H) + ).
General Method for the Reaction of an Aryl Amine with Phosgene with Isolation
of the Isocyanate, Followed by Reaction with a Second Aryl Amine
S0 2 CHF 2
Step 1. 5-(Difluoromethanesulfonyl)-2-methoxyphenyl isocyanate: To a solution
of phosgene (1.95 M in toluene; 3.0 mL, 5.9 mmol) in CH 2 C1 2 (40 mL) at 0 °C was
added a solution of 5-(difluoromethanesulfonyl)-2-methoxyaniline (0.70 g, 2.95
mmol) and pyridine (0.44 mL, 8.85 mmol) in CH 2 C1 2 (10 mL) dropwise. After being
stirred at 0 °C for 30 min and at room temp, for 3 h, the reaction mixture was
concentrated under reduced pressure, then treated with toluene (50 mL). The resulting
MeO
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mixture was concentrated under reduced pressure, then was treated with Et 2 0 (50 mL)
to produce a precipitate (pyridinium hydrochloride). The resulting filtrate was
concentrated under reduced pressure to provide the title compound as a white solid
(0.33 g). This material was used in the next step without further purification.
CHF 2
o=s-o
Step 2. 7V-(2-Methoxy-5-(difluoromethanesulfonyl)phenyl)-iV , -(2-fluoro-4-
methylphenyl)urea: 2-Fluoro-4-methylaniline (0.022 mL, 0. 1 9 mmol) was added to
a solution of 5-(difluoromethanesulfonyl)-2-methoxyphenyl isocyanate (0.046 g, 0.17
mmol) in EtOAc (1 mL). The reaction mixture was stirred at room temp, for 3 d. The
10 resulting precipitate was washed with Et 2 0 to provide the title compound as a white
solid (0.055 g): *H-NMR (CDC1 3 ) 8 2.24 (s, 3H), 4.01 (s, 3H), 6.93 (d, J=8.5 Hz, 1H),
7.01-7.36 (m, 3H), 7.56 (dd 5 7=2.4, 8.6 Hz, 1H), 7.98 (app t, J±&.6 Hz, 1H), 8.79 (d,
J-2.2 Hz, 1H), 9.07 (s, 1H), 9.26 (s, 1H); FAB-MS m/z 389 ((M+l) + ).
lB3b. General Method for the Reaction of an Aryl Amine with Phosgene with Isolation
of the Isocyanate, Followed by Reaction with a Second Aryl Amine
CF 3
NCO
MeO
Step 1. 2-Methoxy-5-trifluoromethylphenyl Isocyanate: To a solution of
phosgene (1.93 M in toluene; 16 mL, 31.4 mmol) in CH 2 C1 2 (120 mL) at 0 °C was
20 added a solution of 2-methoxy-5-(trifluoromethyl)aniline (3.0 g, 15.7 mmol) and
pyridine (2.3 mL, 47.1 mmol) in CH 2 C1 2 (30 mL) dropwise. The resulting mixture was
stirred at 0 °C for 30 min and at room temp for 3 h, then concentrated under reduced
pressure. The residue was diluted with toluene (30 mL), concentrated under reduced
pressure, and treated with E^O. The resulting precipitate (pyridinium hydrochloride)
25 was removed and the filtrate was concentrated under redeuced pressure to give the
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title compound as a yellow oil (3.0 g) which crystallized upon standing at room temp,
for a few days.
Step 2. 7V-(2-Methoxy-5-(trifluoromethyl)phenyl)- 7VH4-fluorophenyl)urea: 4-
Fluoroaniline (0.24 mL, 2.53 mmol) was added to a solution of 2-methoxy-5-
(trifluoromethyl)phenyl isocyanate (0.50 g, 2.30 mmol) in EtOAc (6 mL) and the
reaction mixture was stirred at room temp, for 3 d. The resulting precipitate was
washed with Et 2 0 to give the title compound as a white solid (0.60 g): NMR: 3.94 (s,
3H). 7.13-7.18 (m, 3H), 7.30 (dd, J=1.5, 8.4 Hz, 1H), 7.44 (m, 2H), 8.45 (s, 1H), 8.52
(d, J=2.2 Hz, 1H), 9.42 (s, 1H); FAB-MS m/z 329 ((M+l) + ).
General Method for Urea Formation via Curtius Rearrangement, Followed by
Trapping with an Amine
A^-(3-Methoxy-2-naphthyl)-A r -(4-methylphenyl)urea: To a solution of 3-methoxy-
2-naphthoic acid (Method A6, Step 2; 0.762 g, 3.80 mmol) and Et 3 N (0.588 mL, 4.2
mmol) in anh toluene (20 mL) at room temp, was added a solution of
diphenylphosphoryl azide (1.16 g, 4.2 mmol) in toluene (5 mL). The resulting mixture
was heated to 80 °C for 2 h, cooled to room temp., and /?-toluidine (0.455 g, 4.1
mmol) was added. The mixture was heated at 80 °C overnight, cooled to room temp.,
quenched with a 10% citric acid solution, and extracted with EtOAc (2 x 25 mL). The
combined organic layers were washed with a saturated NaCl solution (25 mL), dried
(MgSOJ, and concentrated in vacuo. The residue was triturated with CH 2 C1 2 to give
the desired urea as white powder (0.700 g, 61%): mp 171-172 °C; 'H-NMR (DMSO-
d 6 ) 5 2.22 (s, 3H), 3.99 (s, 3H), 7.07 (d, J=8.49 Hz, 2H), 7.27-7.36 (m, 5H), 7.67-7.72
(m, 2H), 8.43 (s, 1H), 8.57 (s, 1H), 9.33 (s, 1H); FAB-MS m/z 307 ((M+H) + ).
CF 3
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B5. General Method for the Reaction of Substituted Aniline with N,N'-
Carbonyldiimidazole Followed by Reaction with a Second Amine
C
i ii ii
iV-(5-Chloro-2-hydroxy-4-nitrophenyl)-A r '-(4-(4-pyridinylmethyl)phenyl)urea: A
5 solution of 4-(4-pyridinylmethyl)aniline (0.300 g, 1.63 mmol) and N,N'-
carbonyldiimidazole (0.268 g, 1.65 mmol) in CH 2 C1 2 (10 mL) was stirred at room
temp, for 1 h at which time TLC analysis indicated no starting aniline. The reaction
mixture was then treated with 2-amino-4-chloro-5-nitrophenol (0.3 1 8 g, 1 .65 mmol)
and stirred at 40-45 °C for 48 h. The resulting mixture was cooled to room temp, and
10 diluted with EtOAc (25 mL). The resulting precipitate was separated to give the
desired product (0.416 g, 64%): TLC (50% acetone/50% CH 2 C1 2 ) 0.40; 'H-NMR
(DMSO-d 6 ) 8 3.90 (s, 2H), 7.18 (d, J=8.4 Hz, 2H), 7.21 (d, J=6 Hz, 2H), 7.38 (d, 7=8.4
Hz, 2H), 7.54 (s, 1H), 8.43-8.45 (m, 3H), 8.78 (s, 1H), 9.56 (s, 1H), 11.8 (br s, 1H);
FAB-MS m/z (rel abundance) 399 ((M+H) + , 10%).
15
B6. General Method for the Synthesis of Symmetrical Diphenyl Ureas as Side-
Products of Urea Forming reactions
Bis(4-chloro-3-(trifluoromethyl)phenyl)urea: To a solution of 5-arnino-3-tert-
20 butylisoxazole (0.100 g) in anh toluene (5 mL) was added 4-chloro-3-
(trifluoromethyl)phenyl isocyanate (0.395 g). The reaction vessel was sealed, heated
at 85 °C for 24 h, and cooled to room temp. The reaction mixture was added to a
slurry of Dowex® 50WX2-100 resin (0.5 g) in CH 2 C1 2 (40 mL), and the resulting
mixture was stirred vigorously for 72 h. The mixture was filtered and the filtrate was
25 concentrated under reduced pressure. The residue was purified by column
chromatography (gradient form 100% CH 2 C1 2 to 5% MeOH/95% CH 2 C1 2 ) to give
bis(4-chloro-3-(trifluoromethyl)phenyl)urea followed by ^-(3-rert-butyl-5-
isoxazolyl)-7V'-(4-chloro-3-(trifluoromethyl)phenyl)urea. The residue from the
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symmetrical urea fractions was triturated (Et 2 0/hexane) to give the urea as a white
solid (0.1 10 g): TLC (3% MeOH/97% CH 2 C1 2 ) R r 0.55; FAB-MS m/z 417 ((M+H) + ).
B. Combinatorial Method for the Synthesis of Diphenyl Ureas Using
Triphosgene
One of the anilines to be coupled was dissolved in dichloroethane (0.10 M). This
solution was added to an 8 mL vial (0.5 mL) containing dichloroethane (1 mL). To
this was added a triphosgene solution (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv.),
followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.).
The vial was capped and heated at 80°C for 5 h, then allowed to cool to room temp,
for approximately 10 h. The second aniline was added (0.10 M in dichloroethane, 0.5
mL, 1.0 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2
mL, 1 .2 equiv.). The resulting mixture was heated at 80°C for 4 h, cooled to room
temperature and treated with MeOH (0.5 mL). The resulting mixture was
concentrated under reduced pressure and the products were purified by reverse phase
HPLC.
C. Urea Interconversions and Misc. Reactions
CI. General Method for Alkylation of Hydroxyphenyl Ureas
SCF 3
Step 1 . 7V-(2-Hy droxy-5-(trifluoromethylthio)pheny IHV'-(4-methylpheny l)urea:
p-Tolyl isocyanate (0.066 mL, 0.52 mmol) was added to a solution of 2-hydroxy-5-
(trifluoromethylthio)aniline (0.100 g, 0.48 mmol) in EtOAc (2 mL) and the reaction
mixture was stirred at room temp, for 2 d. The resulting precipitate was washed with
EtOAc to provide the title compound (0.13 g): 'H-NMR (CDC1 3 ) 5 2.24 (s, 3H). 7.44-
7.03 (m, 6H), 8.46 (s, 1H), 8.60 (d, J=1.8 Hz, 1H), 9.16 (s, 1H), 10.41 (s, 1H); FAB-
MS m/z 343 ((M+l) + ). This material was used in the next step without purification.
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Step 2.AH2-Methoxy-5-(trifluoromethy^
A solution of A r -(2-hydroxy-5-(trifluoromethylthio)phenyl)-A' r -(4-methylphenyl)urea
(0.125 g, 0.36 mmol), iodomethane (0.045 mL, 0.73 mmol), and K 2 C0 3 (100 mg, 0.73
mmol) in acetone (2 mL) was heated at the reflux temp, for 6 h, then was cooled to
room temp, and concentrated under reduced pressure. The residue was dissolved in a
minimal amount of MeOH, absorbed onto silica gel, and then purified by flash
chromatograpy (3% Et 2 0/97% CH 2 C1 2 ) to provide the title compound as a white solid
(68 mg): 'H-NMR (CDC1 3 ) 8 2.22 (s, 3H), 3.92 (s, 3H), 7.05-7.32 (m, 6H), 8.37 (s,
1H), 8.52 (d, 7=2.2 Hz, 1H), 9.27 (s, 1H); FAB-MS m/z 357 ((M+l) + ).
C2. General Method for the Reduction of Nitro-Containing Ureas
A r -(5-^rr-Butyl-2-methoxyphenyl)-A^ , -(2-amino-4-methylphenyl)urea: A solution
of A^-(5-/er/-butyl-2-methoxyphenyl)-A' r '-(2-nitro-4-methylphenyl)urea (prepared in a
manner analogous to Method Bla; 4.0 g, 11.2 mmol) in EtOH (100 mL) was added to
a slurry of 10% Pd/C (0.40 g) in EtOH (10 mL), and the resulting mixture was stirred
under an atmosphere of H 2 (balloon) at room temp, for 18 h. The mixture was filtered
through a pad of Celite® and concentrated in vacuo to afford the desired product (3.42
g, 94%) as a powder: mp 165-166 °C; 'H-NMR (DMSO-d 6 ) 5 1.30 (s, 9H), 2.26 (s,
3H), 3.50 (br s, 2H), 3.71 (s, 3H), 6.39 (br s, 1H), 6.62 (s, 1H), 6.73 (d, J=8.46 Hz,
1H), 6.99 (dd, J=2.21, 8.46 Hz, 1H), 7.05 (d, J-8.46 Hz, 1H), 7.29 (s, 1H), 8.22 (d,
7=2.57 Hz, 1H); FAB-MS m/z 328 ((M+H) + ).
C3. General Method of Thiourea Formation by Reaction with a
Thioisocyanate
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MeO
AT_(5_^_Butyl-2-methoxyphenyl)-A r -(l-naphthyl)thiourea: To a solution of 5-
ter^butyl-2-methoxyaniline (0.372 g, 2.07 mmol) in toluene (5 mL) was added 1-
naphthyl thioisocyanate (0.384 g, 2.07 mmol) and the resulting mixture was allowed
to stir at room temp, for 8 h to produce a precipitate. The solids were separated and
sequentially washed with toluene and hexane to give the desired product as an off-
white pwoder (0.364 g, 48%): mp 158-160 °C; 'H-NMR (DMSO-d 6 ) 6 1.31 (s, 9H),
3.59 (s, 3H), 6.74 (d, .7=8.46 Hz, 1H), 7.13 (dd, 7=2.21, 8.46 Hz, 1H), 7.53-7.62 (m,
4H), 7.88-7.95 (m, 4H), 8.06-8.08 (m, 1H), 8.09 (br s, 1H); FAB-MS m/z 365
((M+H) + ).
C4. General Method for Deprotection of terf-Butyl Carbonate-Containing
Ureas
A^-(5-rerr-Butyl-2-(2-hydroxyethoxy)phenyl)-A r, -(4-methyIphenyl)urea: A solution
of iV-(5-re^butyl-2-(2-^rr-butoxycarbonyloxy)ethoxy)phenyl)-7V f -(4-
methylphenyl)urea (Method Blf; 0.237 g, 0.54 mmol) and TFA (0.21 mL, 2.7 mmol)
in CH 2 C1 2 (2 mL) was stirred at room temp for 1 8 h, then was washed with a saturated
NaHC0 3 solution (2 mL). The organic layer was dried by passing through IPS filter
paper (Whatman®) and concentrated under reduced pressure. The resulting white
foam was triturated (EtjO/hexane), then recrystallized (EtjO) to give the desired
product (3.7 mg): TLC (50% EtOAc/50% hexane) 0.62; *H-NMR (DMSO-d 6 ) 6
1.22 (s, 9H), 3.75-3.76 (m, 2H), 4.00-4.03 (m, 2H), 4.80 (t, J=5.0 Hz, 1H), 6.88-6.89
(m, 4H), 7.06 (d, 7=8.5 Hz, 2H), 7.33 (d, J=SA Hz, 2H), 7.97 (s, 1H), 8.20 br s, 1H),
9.14 (s, 1H); FAB-MS m/z (rel abundance) 343 ((M+H) + , 100%).
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The following compounds have been synthesized according to the General Methods
listed above:
Table 1. 2-Substituted-5-terf-butylptaenyI Ureas
5
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13
14
-o-so
185-
186
145-
147
A7,Bla
A7,Bla
15
H
HC1
0.77 1 50% 378
(free EtOAc J (M+H)+
amine) | 50% pet
ether
FAB
Bla
16
H
-Q-o-Q
376
(M+H)-
FAB
B5
Me
17
18
H
H
362
(M+H)+
HPLC
ES-MS
B5
10.80 1 50%
EtOAc
50% pet
ether
405
y(M+H)+
HPLC
ES-MS
B5
19
H
Me
210
HC1
0.13 30%
free EtOAc
amine) | 70% pet
ether
376
/(M+H)+
FAB
B5
20
H
3.94
50%
EtOAc
50%
hexane
362
y(M+H)+
HPLC
ES-MS
B5
21
H
-O-o-Q
Me
141
75%
EtOAc
25%
hexane
376
/(M+H)+
HPLC
ES-MS
B5
22
H
114- 10.38
117
30%
EtOAc
70%
hexane
404
y(M+H)+
HPLC
ES-MS
A14c,
23
H
346
(M+H)+
HPLC
ES-MS
B5
24
H
O-^ /hMe
N
3.14
50%
EtOAc
50%
hexane
376
J
HPLC
ES-MS
B5
25
26
Me
-■6
Me
190-
195
3.56
Me
Me
Me
194-
197
3.55
75%
EtOAc
25%
hexane
455
y(M+H)+
75%
EtOAc
25%
hexane
HPLC
ES-MS
B5
469
I (M+H)+
HPLC
ES-MS
B5
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Table 2.
2-Substituted-5-(trifluoromethyl)phenyI Ureas
CF 3
Entry
R 1
R 2
mp
(°C)
TLC
Solvent
System
Mass
Spec.
Synth.
Source I Method
27
OMe
184-
185
401
(M+H)+
FAB
B2a
28
OMe
231-
233
361
(M+H)+
FAB
Bla
29
OMe
O
Me
198
417
(M+H)+
FAB
Ble
30
OMe
o
ci
206 0.58
5%
acetone
95%
CH2C12
437
(M+H)+
FAB
B2a
31
OMe
-o°-co
98-99 0.50
5%
acetone
95%
CH2C12
B2a
32
OMe
226 0.49
5%
acetone
95%
CH2C12
460
(M+H)+
FAB
B2a
33
OMe
O
OMe
190 0.65
5%
acetone
95%
CH2C12
B2a
34
OMe
194 0.76
5%
acetone
95%
CH2C12
464
(M+H)+
FAB
B2a
35
OMe
210- I 0.07
211
5%
acetone
95%
CH2C12
402
(M+H)+
FAB
B2a
36
OMe
202 0.09
5%
acetone
95%
CH2C12
420
(M+H)+
FAB
B2a
37
OMe
215 0.08
5%
acetone
95%
CH2C12
420
(M+H)+
FAB
B2a
38
OMe
-0-<K>
206 0.05
5%
acetone
95%
CH2C12
404
(M+H)+
FAB
B2a
64
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39
OMe
Me
60-62 0.86
-o-«-o
5%
acetone I
95%
CH2C12
433
(M+H)+
FAB
Bla
40
OMe
Me
173- I 0.83
176
5%
acetone I
95%
CH2C12
417
(M+H)+
FAB
Bla
41
OMe
426
(M+H)+
FAB
B5
42
OMe
198-
200
0.75 5%
431
FAB
Me
acetone \ (M+H)+
95%
CH2C12
B3b
43
OMe
169-
171
0.03
50%
EtOAc
50%
hexane
402
(M+H)+
FAB
B5
44
OMe
CI
0.18
5%
acetone
95%
CH2C12
456
(M+H)+
FAB
B3b
45
OMe
Me
161-
162
0.73
5%
acetone
95%
CH2C12
417
(M+H)+
FAB
B3b
46
OMe
0.44
Me
5%
acetone
95%
CH2C12
418
(M+H)+
FAB
B3b
47
OMe
487
(M+H)+
FAB
F^C
B3b
48
OMe
CF,
0.35
5%
acetone
95%
CH2C12
472
(M+H)+
FAB
B3b
49
50
OMe
0.91
5%
acetone
95%
CH2C12
455
(M+H)+
FAB
OMe
-Q-K>
0.78
5%
acetone
95%
CH2C12
437
(M+H)+
FAB
B3b
B3b
51
OMe
CF 3
0.82
5%
acetone
95%
CH2C12
471
(M+H)+
FAB
B3b
52
OMe
-<>o-o
189- I 0.76
190
F,C
5%
acetone
95%
CH2C12
471
(M+H)+
FAB
B3b
65
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53
OMe
O
^ A
SMe
186-
188
0.30
20%
EtOAc
80%
CH2C12
449
(M+H)+
HPLC
ES-MS
B5
54
55
OMe
0.53
100%
EtOAc
434
(M+H)+
HPLC
ES-MS
OMe
223- I 0.22
224
5%
MeOH
45%
EtOAc
50% pel
ether
427
(M+H)+
HPLC
ES-MS
B5
Ble
56
57
OMe
Me
202- I 0.21
204
5%
MeOH
45%
EtOAc
50% pel
ether
418
(M+H)+
HPLC
ES-MS
OMe
166 0.40
5%
MeOH
95%
CH2C12
454
(M+H)+
FAB
B5
B5
58
OMe
0.67
50%
EtOAc
50% pel
ether
434
(M+H)+
HPLC
ES-MS
B5
59
OMe
Me
b "0
210- I 0.19
212
100%
EtOAc
418
(M+H)+
HPLC
ES-MS
B5
60
OMe
b -0
203-
205
0.80
50%
EtOAc
50%
hexane
404
(M+H)+
HPLC
ES-MS
B5
61
62
OMe
235-
236
0.51
10%
MeOH
90%
CH2C12
488
(M+H)+
HPLC
ES-MS
OMe
— <^Vo-^^-SMe
205-
207
0.59
10%
MeOH
90%
CH2C12
450
(M+H)+
HPLC
ES-MS
B5
B5
63
OMe
-Q-O-Q-Me
214-
216
0.59
10%
MeOH
90%
CH2C12
418
(M+H)+
HPLC
ES-MS
B5
64
65
OMe
f \
0.56
10%
MeOH
90%
CH2C12
422
(M+H)+
HPLC
ES-MS
OMe
209- I 0.63
211
10%
MeOH
90%
CH2C12
B5
B5
66
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66
OMe
196-
198
0.54
10%
MeOH
90%
CH2C12
418 (M+) CI
B5
67
OMe
0-4 >-OMe
215-
217
0.11
2%
MeOH
98%
CH2C12
434
(M+H>
FAB
B5
68
OMe
O
CI
226-
228
0.13
2%
MeOH
98%
CH2C12
438
(M+H)+
FAB
B5
69
OMe
211-
213
0.08
2%
MeOH
98%
CH2C12
404
(M+H)+
FAB
B5
70
OMe
216-
217
0.53
100%
EtOAc
488
(M+H)+
HPLC
ES-MS
B5
71
OMe
Me /=
N
147 0.20
OMe
30%
EtOAc
70%
hexane
446
(M+H)+
HPLC
ES-MS
B5
72
OMe
-<>o-Qnh
o
215-
220
420
(M+H)+
FAB
B5
73
OMe
OH
0.14
50%
EtOAc
50%
hexane
419
(M+H)+
FAB
B5
74
OMe
0.07
50%
EtOAc
50%
hexane
402
FAB
B5
75
OMe
0.08
50%
EtOAc
50%
hexane
418
HPLC
ES-MS
B5
76
OMe
165-
169
0.05
50%
EtOAc
50%
hexane
404
FAB
B5
77
OMe
HO
0.26
50%
EtOAc
50% pe
ether
419
(M+H)+
HPLC
ES-MS
B5
78
OMe
-O s -Q
0.20
50%
EtOAc h
50% pe
ether
All
(M+H)+
HPLC
ES-MS
B5
79
OMe
125- I 0.18
127
5%
MeOH
95%
CH2C12
420
(M+H)+
HPLC
ES-MS
B5
67
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80
OMe
197-
1 QC
B5
81
H
142-
143
0.30
100%
EtOAc
374
(M+H)+
HPLC
ES-MS
B5
82
CI
-0~ oH C N
149-
152
0.48
100%
EtOAc
408
(M+H)+
HPLC
ES-MS
B5
83
F
-0-°"C N
185-
186
0.28
100%
EtOAc
392
1 (M+H)+
HPLC
ES-MS
B5
68
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Table 3.
2-Substituted»5-(trifluoromethyl)phenyI Ureas
CF 3
85
86
£1
CI
CI
CI
OH^ />-Me
N
S
Me
mp
TLC
(°C)
R f
199-
0.66
201
Solvent | Mass
System 1 Sp ec.
20% 423
MeOH l\ (M+H)+
80%
CH2C12 _^
430
(M+H)+
Synth.
Source 1 Me thod
FAB |B5
FAB
B5
422 I FAB
(M+H)+
B5
87
CI
S-\ )"OMe
454 I FAB
(M+H)+
B5
88
CI
OH
423 I FAB
(M+H)+
B5
89
CI
422
(M+H)+
FAB
B5
90
91
92
93
94
95
96
CI
0-\ /^SMe
CI
Me
CI
168-
170
0.30
0.38
20% I 453
EtOAc /| (M+H)+
80%
CH2C12
100% [422
EtOAc I (M+H)+
209-
212
0.24
CI
"<IVo-0-OMe
CI
CI
CI
5%
MeOH /I
45%
EtOAc /I
50% pet|
ether
431
(M+H)+
HPLC ES-I
MS
HPLC ES-IB5
MS
HPLC ES-lBle
MS
0.44 | 50%
EtOAc /I
50% pet|
ether
0.43 | 50%
EtOAc /[
50% pet|
ether
438
(M+H)+
458
(M+H)+
HPLC ES-IB5
MS
HPLC ES-|B5
MS
0.33 | 50%
EtOAc /[
50% pet|
ether
442
(M+H)+
HPLC ES-IB5
MS
0.56 | 50%
EtOAc /[
50% petj
ether
440
(M+H)+
HPLC ES-IB5
MS
69
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97
CI
0.51 I 50%
EtOAc /I
50% pet |
ether
419
(M+H)+
HPLC ES-IB5
MS
98
CI
-o-O
0.24 I 50%
EtOAc /\
50% pet I
ether
425
(M+H)+
HPLC ES-IB5
MS
99
CI
-0°-Q
HO
0.35 | 50%
EtOAc /I
50% pet]
ether
423
(M+H)+
HPLC ES-IB5
MS
100
CI
169-
171
0.14
100%
EtOAc
424
(M+H)+
FAB
B5
101
CI
— (QhMe
179-
180
0.26
100%
EtOAc
422
(M+H)+
HPLC ES-IB5
MS
102
CI
181-
183
0.22 | 5%
MeOH /I
95%
CH2C12
408
(M+H)+
FAB
B5
103
CI
0.27
70%
EtOAc
30%
hexane
437
/I (M+H)+
HPLC ES-IB5
MS
104
CI
118-
120
0.17 I 5%
MeOH /I
95%
CH2C12
458
(M+H)+
HPLC ES-IB5
MS
105
CI
0.21 | 30%
EtOAc /I
70% pet|
ether
420
(M+H)+
HPLC ES-IB5
MS
106
107
CI
CI
Me
bH C N
172-
173
0.17 | 10%
MeOH /I
90%
CH2C12
422
(M+H)+
FAB
B5
184-
185
0.11 | 10%
MeOH /I
90%
CH2C12
408
(M+H)+
FAB
B5
108
CI
126-
128
0.70 I 20%
MeOH /I
80%
CH2C12
408
(M+H)+
FAB
B5
109
CI
-0" s -C N
0.54
50%
EtOAc
50%
hexane
424
/I (M+H)+
HPLC ES-IB5
MS
110
CI
Me Me
0.11
50%
EtOAc
50%
hexane
436
/I (M+H)+
HPLC ES-IB5
MS
70
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111
CI
-^Yo^
■t a 1
191-
193
A 1 *7
0.17
CO/
MeOH /
95%
CH2C12
112
CI
207-
209
0.43
100%
EtOAc
492
(M+H)+
HPLC ES-
MS
B5
113
CI
0.28
100%
EtOAc
435
(M+H)+
HPLC ES-
MS
B5
114
CI
Ivle
163-
166
A CO
A AO/
40%
EtOAc /
60%
hexane
(M+H)+
MS
A 1 An Ti ^
115
CI
one
207
u.oy
J /o
acetone /
95%
CH2C12
AOA
(M+H)+
1? AT)
116
CI
0.06
50%
EtOAc /
50%
hexane
406
FAB
B5
117
CI
F 3 C
4 /o
(M+H)+
DJ
118
Br
115-
117
0.28
100%
EtOAc
452
(M+H)+
HPLC ES-
MS
119
F
171-
172
0.31
100%
EtOAc
392
(M+H)+
HPLC ES-
MS
71
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Table 4
3-Substituted-2-naphthyl Ureas
Entry
R 1
mp
(°C)
TLC
Solvent
System
Mass
Spec.
Source
Synth.
Method
120 OMe
238-
239
0.25
25%
EtOAc
75%
hexane
402
(M+H)+
FAB
B4
121 OMe
199-
200
0.20
25%
EtOAc
75%
hexane
384
(M+H)+
FAB
B4
122 OMe
^ ^0-\ /J^OMe
209-
211
0.40
25%
EtOAc
75%
hexane
414 (M+) EI
B4
123 OMe
O
401
(M+H)+
FAB
B5
OH
124 OMe
0.05
50%
EtOAc
50%
hexane
384
(M+H)+
FAB
B5
125 OMe
0.86
50%
EtOAc
50% pe
ether
415
(M+H)+
HPLC
ES-MS
B5
126 OMe
-Q _
s ~C N
0.76
50%
EtOAc
50% pe
ether
402
(M+H)+
HPLC
ES-MS
B5
127 OMe
0.39
50%
EtOAc
50%
hexane
386
(M+H)+
HPLC
ES-MS
B5
128 OMe
Me^
0.30
75%
EtOAc
25%
hexane
400
(M+H)+
HPLC
ES-MS
B5
129 OMe
Me /=
130 0.28
N-\ /-OMe
30%
EtOAc
70%
hexane
428
(M+H)+
HPLC
ES-MS
B5
130 OMe
Me
0.14
50%
EtOAc
50%
hexane
400
(M+H)+
FAB
B5
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Table 5. Additional Ureas
Entry
Urea
mp
(°C)
TLC
Solvent
System
Mass
Spec.
Source
Synth.
Method
131
CF 3 CF,
MeO H H OMe
CI
0.57 I 5%
MeOH
45%
EtOAc
50% pet
ether
477
(M+H)+
HPLC
ES-MS
Ble
132
CI
MeO H H
0.21 I 5%
MeOH
45%
EtOAc
50% pet
ether
438
(M+H)+
HPLC I Ble
ES-MS
133
134
135
136
H H
0.34
100%
EtOAc
404
(M+H)+
HPLC
ES-MS
Ble
CI
CI
H H
0.11 I 100%
EtOAc
374
(M+H)+
HPLC
ES-MS
Ble
Br
0.26
CI
100%
EtOAc
418
(M+H)+
HPLC
ES-MS
Ble
N N
H H
O
CF:
0.33
100%
EtOAc
390
(M+H)+
HPLC
ES-MS
Ble
N N
H H
137 0?N
MeO H H
0.26
100%
EtOAc
381
(M+H)+
HPLC I Ble
ES-MS
138
N0 2
0.13
100%
EtOAc
381
(M+H)+
HPLC I Ble
ES-MS
MeO H H
139
0 2 N
CI
0.42
100%
EtOAc
385
(M+H)+
HPLC I Ble
ES-MS
H H
140
MeO H H
0.43
100%
EtOAc
370
(M+H)+
HPLC I Ble
ES-MS
141
CF,
0.21
F,C
H H
30%
EtOAc/
70%
pet ether
420
(M+H)+
HPLC I Ble
ES-MS
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142
° 2N Til s rTrt
HO H H
0.40
50%
acetone/
50%
emeu
399
(M+H)+
FAB
B5
143
H H
224
0.87
5%
acetone/
95%
465
(M+H)+
FAB
B6
144
O
H H
0.10
50%
EtOAc/
pet ether
394
(M+H)+
HPLC
ES-MS
B5
BIOLOGICAL EXAMPLES
In Vitro raf Kinase Assav :
In an in vitro kinase assay, raf was incubated with MEK in 20 mM Tris-HCl, pH 8.2
5 containing 2 mM 2-mercaptoethanol and 100 mM NaCl. This protein solution (20
p.L) was mixed with water (5 \iL) or with compounds diluted with distilled water from
10 mM stock solutions of compounds dissolved in DMSO. The kinase reaction was
initiated by adding 25 ^iL [y- 33 P]ATP (1000-3000 dpm/pmol) in 80 mM Tris-HCl, pH
7.5, 120 mM NaCl, 1.6 mM DTT, 16 mM MgCl 2 . The reaction mixtures were
10 incubated at 32 °C, usually for 22 min. Incorporation of 33 P into protein was assayed
by harvesting the reaction onto phosphocellulose mats, washing away free counts with
a 1% phosphoric acid solution and quantitating phosphorylation by liquid scintillation
counting. For high throughput screening, 10 jjM ATP and 0.4 j^M MEK was used. In
some experiments, the kinase reaction was stopped by adding an equal amount of
15 Laemmli sample buffer. Samples were boiled 3 min and the proteins resolved by
electrophoresis on 7.5% Laemmli gels. Gels were fixed, dried and exposed to an
imaging plate (Fuji). Phosphorylation was analyzed using a Fujix Bio-Imaging
Analyzer System.
20 All compounds exemplified displayed IC 50 s of between 1 nM and 10 \iM.
Cellular Assav :
For in vitro growth assay, human tumor cell lines, including but not limited to
HCT116 and DLD-1, containing mutated K-ras genes were used in standard
25 proliferation assays for anchorage dependent growth on plastic or anchorage
74
WO 99/32436
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independent growth in soft agar. Human tumor cell lines were obtained from ATCC
(Rockville MD) and maintained in RPMI with 10% heat inactivated fetal bovine
serum and 200 mM glutamine. Cell culture media and additives were obtained from
Gibco/BRL (Gaithersburg, MD) except for fetal bovine serum (JRH Biosciences,
Lenexa, KS). In a standard proliferation assay for anchorage dependent growth, 3 X
10 3 cells were seeded into 96-well tissue culture plates and allowed to attach
overnight at 37 °C in a 5% C0 2 incubator. Compounds were titrated in media in
dilution series and added to 96-well cell cultures. Cells were allowed to grow 5 days
typically with a feeding of fresh compound containing media on day three.
Proliferation was monitored by measuring metabolic activity with standard XTT
colorimetric assay (Boehringer Mannheim) measured by standard ELISA plate reader
at OD 490/560, or by measuring 3 H-thymidine incorporation into DNA following an 8
h culture with 1 |j.Cu 3 H-thymidine, harvesting the cells onto glass fiber mats using a
cell harvester and measuring 3 H-thymidine incorporation by liquid scintillant
counting.
For anchorage independent cell growth, cells were plated at 1 x 10 3 to 3 x 10 3 in 0.4%
Seaplaque agarose in RPMI complete media, overlaying a bottom layer containing
only 0.64% agar in RPMI complete media in 24-well tissue culture plates. Complete
media plus dilution series of compounds were added to wells and incubated at 37 °C
in a 5% C0 2 incubator for 10-14 days with repeated feedings of fresh media
containing compound at 3-4 day intervals. Colony formation was monitored and total
cell mass, average colony size and number of colonies were quantitated using image
capture technology and image analysis software (Image Pro Plus, media Cybernetics).
In Vivo Assay :
An in vivo assay of the inhibitory effect of the compounds on tumors (e.g., solid
cancers) mediated by raf kinase can be performed as follows:
CDI nu/nu mice (6-8 weeks old) are injected subcutaneously into the flank at 1 x 10 6
cells with human colon adenocarcinoma cell line. The mice are dosed i.p., i.v. or p.o.
at 10, 30, 100, or 300 mg/Kg beginning on approximately day 10, when tumor size is
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between 50-100 mg. Animals are dosed for 14 consecutive days once a day; tumor
size was monitored with calipers twice a week.
The inhibitory effect of the compounds on raf kinase and therefore on tumors (e.g.,
solid cancers) mediated by raf kinase can further be demonstrated in vivo according to
the technique of Monia et al. (Nat. Med. 1996, 2, 668-75).
The preceding examples can be repeated with similar success by substituting the
genetically or specifically described reactants and/or operating conditions of this
invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential
characteristics of this invention and, without departing from the spirit and scope
thereof, can make various changes and modifications of the invention to adapt it to
various usages and conditions.
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WHAT IS CLAIMED IS:
1. A compound of formula I:
wherein
A is
R 3 , R 4 , R 5 and R 6 are each, independently, H, halogen, N0 2 , C M0 - alkyl, optionally
substituted by halogen up to perhaloalkyl, C^o-alkoxy, optionally
substituted by halogen up to perhaloalkoxy, aryl, optionally
substituted by C,. 10 alkyl or Cj_ 10 alkoxy, or C 5 _i 2 hetaryl,
optionally substituted by Ci_ 10 alkyl or C M0 alkoxy,
and one of R 3 -R 6 can be -X-Y;
or two adjacent R 3 -R 6 can together be an aryl or hetaryl ring with 5-12 atoms,
optionally substituted by C M0 -alkyl, C^o-alkoxy, C 3 . 10 -cycloalkyl, C 2-10 -alkenyl,
C M0 -alkanoyl, C M2 -aryl, C 5 . 12 -hetaryl; C^-aralkyl, C^-alkaryl, halogen; NR'R 1 ;
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-NO z ; -CF 3 ; -COOR 1 ; -NHCOR 1 ; -CN; -CONR'R 1 ; -S0 2 R 2 ; -SOR 2 ; -SR 2 ; in which R 1
is H or C,., 0 -alkyl and R 2 is C,. I0 -alkyl, optionally substituted by halogen, up to
perhalo with -S(0 2 )- optionally incorporated in the aryl or hetaryl ring;
R 4 ' , R 5 ' and R 6 ' are independently H, halogen, C, - C 10 alkyl, optionally substituted by
halogen up to perhaloalkyl,
N
\
or —N - NH
o 6
Cj -C 10 alkoxy optionally substituted by halogen up to perhaloalkoxy or -
X-Y, and either one of R 4 ' , R 5 ' or R 6 ' is -X-Y or two adjacent of R 4 ' , R 5 '
and R 6 together are a hetaryl ring with 5-12 atoms optionally substituted
by C,. 10 alkyl, C,., 0 alkoxy, C 3 _ 10 cycloalkyl, C 2 . 10 alkenyl, C M0 alkanoyl,
C 6 . 12 aryl, C 5 _ 12 hetaryl or C^ l2 aralkyl;
R 6 ' is additionally -NHCOR 1 , - NR 1 COR 1 or N0 2 ;
R 1 is C M0 alkyl optionally substituted by halogen up to perhalo;
R 3 ' is H, halogen, C } -C l0 alkyl optionally substituted by halogen up to
perhaloalkyl, C,-C 10 alkoxy, optionally substituted by halogen up to
perhaloalkoxy;
X is -CH 2 -, -S-, -N(CH 3 )-, -NHC(O)- ~CH 2 -S-, -S-CH 2 -, -C(O)-, or -O-; and
X is additionally a single bond where Y is pyridyl; and
Y is phenyl, pyridyl, naphthyl, pyridone, pyrazine, pyrimidine,
benzodiaxane, benzopyridine or benzothiazole, each optionally substituted
by Ci_ 10 -alkyl, C M0 -alkoxy, halogen, OH, -SCH 3 , N0 2 or, where Y is
phenyl, by
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or a pharmaceutically acceptable salt thereof,
with the proviso that if X is -O- or -S- , R
unsubstituted by OH, then R 6 is alkoxy.
y and R 6 are H, and Y is phenyl
2.
A compound according to claim 1, having a pKa greater than 10.
3.
A compound according to claim 1 , wherein
R 3 is halogen or C,., 0 - alkyl, optionally substituted by halogen, up to perhaloalkyl;
R 4 is H, halogen or N0 2 ;
R 5 is H, halogen or C ul0 - alkyl; R 6 is H, C M0 - alkoxy, thiophene, pyrole or methyl
substituted pyrole,
R 3 ' is H, halogen, CH 3 , or CF 3 and R 6 ' is H, halogen CH 3 , CF 3 or -OCH 3
4. A compound according to claim 1, wherein
R 3 is C 4 _i 0 -alkyl, CI, F or CF 3 ;
R 4 is H, CI, F or N0 2 ;
R 5 is H, CI, F or CV 10 -alkyl; and
R 6 is H or OCH 3 .
5. A compound according to claim 4, wherein R 3 or R 5 is t-butyl.
6. A compound according to claim 1, wherein X is -CH 2 - , -N(CH 3 )- or -
NHC(O)-.
7.
A compound according to claim 6, wherein Y is phenyl or pyridyl.
8.
A compound according to claim 1, wherein X is -O-.
9.
A compound according to claim 8, wherein Y is phenyl, pyridyl
pyridone or benzothiazole.
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10. A compound according to claim 1, wherein X is -S-.
11. A compound according to claim 10, wherein Y is phenyl or pyridyl.
12. A compound of the formula
O
13. A pharmaceutical composition comprising a compound of claim 1,
and a physiologically acceptable carrier.
14. A pharmaceutical composition comprising a compound of claim 12,
and a physiologically acceptable carrier.
15. A method for the treatment of a cancerous cell growth mediated by raf
kinase, comprising administering a compound of formula II:
O
II
wherein
A is
R 3 '
B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety
of up to 30 carbon atoms with at least one 6-member aromatic structure containing
0-4 members of the group consisting of nitrogen, oxygen and sulfur, wherein if B is
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substituted it is substituted by one or more substituents selected from the group
consisting of halogen, up to per-halo, and W n , wherein n is 0-3 and each W is
independently selected from the group consisting of -CN, -C0 2 R 7 , -C(0)NR 7 R 7 ,
-C(0)-R 7 , -N0 2 , -OR 7 , - SR 7 , - NR 7 R 7 , -NR 7 C(0)OR\ -NR 7 C(0)R 7 , C r C 10 alkyl,
C 2 -C 10 alkenyl, C r C 10 alkoxy, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 7 -C 24 alkaryl, C 3 -C 13
heteroaryl, Q-C^ alkheteroaryl, substituted C r C 10 alkyl, substituted C 2 -C 10 alkenyl,
substituted C r C 10 alkoxy, substituted C 3 -C 10 cycloalkyl, substituted Q-C^
alkheteroaryl and Q-Ar;
wherein if W is a substituted group, it is substituted by one or more
substituents independently selected from the group consisting of -CN, -C0 2 R 7 , -
C(0)R 7 , -C(0)NR 7 R 7 , -OR 7 , -SR 7 , -NR 7 R 7 , N0 2 , -NR 7 C(0)R 7 , -NR 7 C(0)OR 7 and
halogen up to per-halo;
wherein each R 7 is independently selected from H, C r C 10 alkyl, C 2 -C 10
alkenyl, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 3 -C 13 hetaryl, C 7 -C 24 alkaryl, Q-C^
alkheteroaryl, up to per-halosubstituted C r C 10 alkyl, up to per-halo substituted C 2 -
C 10 alkenyl, up to per-halosubstituted C 3 -C 10 cycloalkyl, up to per-halosubstituted
C 6 -C 14 aryl and up to per-halosubstituted C 3 -C 13 hetaryl,
wherein Q is - O-, -S-, -N(R 7 )-, -(CH 2 )- m , -C(O)-, -CH(OH)-, -(CH^O-,
-NR 7 C(0) NR 7 R 7 -, -NR 7 C(0)-, -C(0)NR 7 -, -(CH 2 ) m S-, -(CEyj^R 7 )-, -OCCH^-,
-CHX a , -CXV, S-iCKJnr and -NCR'XCH^-,
m = 1-3, and X a is halogen; and
Ar is a 5-10 member aromatic structure containing 0-2 members of the group
consisting of nitrogen, oxygen and sulfur, which is unsubstituted or substituted by
halogen up to per-halo and optionally substituted by Z nl , wherein nl is 0 to 3 and
each Z is independently selected from the group consisting of of -CN, -C0 2 R 7 ,
-C(0)NR 7 R\ -C(O)- NR\ -N0 2 , -OR 7 , - SR 7 , - NR 7 R 7 , -NR 7 C(0)0R\ -C(0)R 7 ,
-NR 7 C(0)R\ C r C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 14 aryl, C 3 -C 13 hetaryl, Q-C^
alkaryl, C4-C23 alkheteroaryl, substituted C r C 10 alkyl, substituted C 3 -C 10 cycloalkyl,
substituted C 7 -C 24 alkaryl and substituted Q-C^ alkheteroaryl; wherein the one or
more substituents of Z is selected from the group consisting of -CN, -C0 2 R 7 ,
-C(0)NR 7 R 7 , -OR 7 , -SR 7 , -N0 2 , -NR 7 R 7 , -NR 7 C(0)R 7 and -NR 7 C(0)OR 7 ,
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R 4 ' , R s 'and R 6 ' are each independently H, halogen, C M0 -alkyl, optionally substituted
by halogen up to perhaloalkyl,
or — NH
n
T
° o
d -C 10 alkoxy, optionally substituted by halogen up to perhaloalkoxy
or -X-Y, and
either one of R 4 ' , R 5 ' or R 6 is -X-Y or two adjacent of R 4 ' , R 5 ' and R 6 '
together are a hetaryl ring with 5-12 atoms optionally substituted by C lA0 alkyl, C uxo
alkoxy, C 3 . 10 cycloalkyl, C 2 _ 10 alkenyl, C M0 alkanoyl, aryl, C 5 . 12 hetaryl or
ar alkyl;
R 6 ' is additionally -NHCOR 1 , - NR^OR 1 or N0 2 ;
R 1 is C M0 alkyl optionally substituted by halogen up to perhalo;
R 3 ' is independently H, halogen, C M0 alkyl, optionally substituted by halogen up
to perhaloalkyl, C M0 alkoxy, optionally substituted by halogen up to
perhaloalkoxy;
X is -CH 2 -, -S- -N(CH 3 >, -NHC(O)-, -CH 2 -S-, -C(O)-, or -O-;
X is additionally a single bond where Y is pyridyl; and
Y is phenyl, pyridyl, naphthyl, pyridone, pyrazine, pyrimidine, benzodioxane,
benzopyridine or benzothiazole, each optionally substituted by
C^o-alkyl, C M0 -alkoxy, halogen, OH, -SCH 3 or N0 2 or, where Y is phenyl, by
a pharmaceutically acceptable salt thereof .
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PCT/US98/26081
16. A method according to claim 15, comprising administering a
compound of formula Ha:
Ha
wherein
A is
10
15
20
N
or
R
4'
R
5*
R\ R 4 ,R 5 and R 6 are each independently H, halogen, N0 2 , Cj. 10 - alkyl, optionally
substituted by halogen up to perhaloalkyl, or C M0 -alkoxy, optionally substituted by
halogen up to perhaloalkoxy, aryl, optionally substituted by C M0 alkyl or C M0
alkoxy, or C 5 _ I2 hetaryl, optionally substituted by C M0 alkyl or C U10 alkoxy,
and one of R 3 -R 6 can be -X-Y;
or two adjacent R 3 -R 6 can together be an aryl or hetaryl ring with 5-12 atoms,
optionally substituted by C,. 10 -alkyl, C M0 -alkoxy, C 3 . 10 -cycloalkyl, C 2 . 10 -alkenyl,
C M0 -alkanoyl; C^-aryl, C 5 . 12 -hetaryl, Ce.^-alkaryl, halogen; -NR 1 ^; -N0 2 ; -CF 3 ;
-COOR 1 ; -NHCOR 1 ; -CN; -CONR 1 ^; -S0 2 R 2 ; -SOR 2 ; -SR 2 ; in which R 1 is H or
Q.jo-alkyl, optionally substituted by halogen, up to perhalo and R 2 is C^o-alkyl,
optionally substituted by halogen, up to perhalo, with - S0 2 - optionally incorporated
in the aryl or hetaryl ring, and R 3 '- R 6 ' are as defined in claim 15.
17. A method according to claim 16, wherein
R 3 is halogen or C M0 - alkyl, optionally substituted by halogen, up to perhaloalkyl;
R 4 is H, halogen or N0 2 ;
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R 5 is H, halogen or C M0 - alkyl;
R 6 is H [or] Ci_j 0 - alkoxy, thiophene, pyrole or methylsubstituted pyrole
R 3> is H, halogen, CH 3 , or CF 3 and
R 6 ' is H, halogen, CH 3 , CF 3 or OCH 3 .
18. A method according to claim 16, wherein X is -CH 2 - , [or] -S-, -
N(CH 3 )- or -NHC(O)- and Y is phenyl or pyridyl.
19. A method according to claim 16, wherein X is -O- and Y is phenyl,
pyridone, pyrimidine, pyridyl or benzothiazole.
84
INTERNATIONAL SEARCH REPORT
International application No.
PCT/US98/26081
A. CLASSIFICATION OF SUBJECT MATTER
IPC(6) :C07C 275/24 C07D 213/02, 333/02; A61K 31/17, 31/38, 31/44
US CL :514/352, 438, 482; 546/309; 549/29; 564/47
According to International Patent Classification (IPC) or to both national classification and IPC
R FIELDS SEARCHED
Minimum documentation searched (classification system followed by classification symbols)
U.S. : 514/352, 438, 482; 546/309; 549/29; 564/47
Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
NONE
Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
CAS COMPUTER SEARCH 1966-TO DATE
C. DOCUMENTS CONSIDERED TO BE RELEVANT
Category*
Citation of document, with indication, where appropriate, of the relevant passages
Relevant to claim No.
X
Y
X
Y
X
Y
US 5,429,918 A (SETO et al) 04 July 1995, column 4, compound
(A-14).
US 5,470,882 A (DIXON et al) 28 November 1995, see entire
document.
WO 96/25157 A1(SMITHKLINE BEECHAM CORPORATION) 22
August 1996, see entire document.
1-7
1-7
1-9, 13 and 14
1-9, 13 and 14
1-19
1-19
| | Further documents are listed in the continuation of Box C. | | See patent family annex.
* Special categories of cited documents: "T" later document published after the international filing date or priority
date and not in conflict with the application but cited to understand
•A* document defining the general state of the art which is not considered the principle or theory underlying the invention
to be of particular relevance
m-nrn i* j , ,- , , , i • - . r-t j . "X" document of particular relevance; the claimed invention cannot be
"E* earlier document published on or after the international filing date , r . lt _ ' . , . ,
** considered novel or cannot be considered to involve an inventive step
"L" document which may throw doubts on priority claim(s) or which is wnen document is taken alone
cited to establish the publication date of another citation or other
special reason (as specified) *Y" document of particular relevance; the claimed invention cannot be
considered to involve an inventive step when the document is
"O" document referring to an oral disclosure, use. exhibition or other combined with one or more other such documents, such combination
means being obvious to a person skilled in the art
"P* document published prior to the international tiling date but later than - A - docum ent m em ber of the same patent fam ily
the priority date claimed
Date of the actual completion of the international search
10 MARCH 1999
Date of mailing of the international search report
02 APR 1999
Name and mailing address of the ISA/US
Commissioner of Patents and Trademarks
Box PCT
Washington, D.C. 2023 1
Facsimile No. (703) 305-3230
Authorized officer {^\j4L/x)
ZINNA N. DAVIS ^Tj
Telephone No. (703) 308-1235
Form PCT/ISA/210 (second sheet)(July 1992)*
INTERNATIONAL SEARCH REPORT
International application No.
PCT/US98/26081
Box I Observations where certain claims were found unsearchable (Continuation of item 1 of first sheet)
This international report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons:
1. I 1 Claims Nos.:
' — ' because they relate to subject matter not required to be searched by this Authority, namely:
2. I I Claims Nos.:
' — ■ because they relate to parts of the international application that do not comply with the prescribed requirements to such
an extent that no meaningful international search can be carried out, specifically:
Claims Nos.:
because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).
Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet)
This International Searching Authority found multiple inventions in this international application, as follows:
Please See Extra Sheet.
As all required additional search fees were timely paid by the applicant, this international search report covers all searchable
claims.
As all searchable claims could be searched without effort justifying an additional fee, this Authority did not invite payment
of any additional fee.
As only some of the required additional search fees were timely paid by the applicant, this international search report covers
only those claims for which fees were paid, specifically claims Nos.:
No required additional search fees were timely paid by the applicant. Consequently, this international search report is
restricted to the invention first mentioned in the claims; it is covered by claims Nos.:
Remark on Protest
The additional search fees were accompanied by the applicant's protest.
No protest accompanied the payment of additional search fees.
Form PCT/ISA/210 (continuation of first sheet(l))(July 1992)*
INTERNATIONAL SEARCH REPORT
International application No.
PCT/US98/26081
BOX II . OBSERVATIONS WHERE UNITY OF INVENTION WAS LACKING
This ISA found multiple inventions as follows:
This application contains the following inventions or groups of inventions which are not so linked as to form a single
inventive concept under PCT Rule 13.1. In order for all inventions to be searched, the appropriate additional search
fees must be paid.
Group I, claim(s)l-14, drawn to phenyl urea substituted compounds and compositions.
Group II, claim(s) 15-19, drawn to a method of using urea substituted compounds.
The inventions listed as Groups I and II do not relate to a single inventive concept under PCT Rule 13.1 because, under
PCT Rule 13.2, they lack the same or corresponding special technical features for the following reasons:
There is a lack of a significant common structural moiety in the Groups as recited above to which the claimed utility
may be attributed. The common core in the group is urea. Additionally, the rings systems in the Group II invention
includes monocyclic, bicyclic and tricyclic systems which are not related as a recognized class of compounds.
Accordingly, the requirement of the unity of invention has been because there is more than one single inventive concept
within Groups I and II.
Form PCT/ISA/210 (extra sheet)(July 1992)*
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